Tetrahydro-pyrimidoazepines as modulators of TRPV1

ABSTRACT

Certain tetrahydro-pyrimidoazepine compounds are described, which are useful as TRPV1 modulators. Such compounds may be used in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by TRPV1. Thus, the compounds may be administered to treat, e.g., pain, itch, cough, asthma, or inflammatory bowel disease.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 14/157,671 filed onJan. 17, 2014, which is a continuation of U.S. Ser. No. 11/726,756,filed on Mar. 21, 2007, now U.S. Pat. No. 8,673,895, which claims thebenefit of U.S. Provisional Application No. 60/785,415, filed on Mar.31, 2006, the entire contents of which are incorporated herein byreference in their entireties.

FIELD OF THE INVENTION

The present invention relates to certain tetrahydro-pyrimidoazepinecompounds, pharmaceutical compositions containing them, and methods ofusing them for the treatment of disease states, disorders, andconditions mediated by TRPV1 activity.

BACKGROUND OF THE INVENTION

Transient receptor potential (TRP) channel proteins constitute a largeand diverse family of proteins that are expressed in many tissues andcell types. One TRP channel protein of particular interest is thevanilloid receptor 1 (TRPV1 or VR1), a non-selective Ca⁺² channel thatis the molecular target of vanilloid compounds (e.g., capsaicin andresiniferatoxin). Such vanilloid compounds are known to selectivelydepolarize nociceptors, specialized primary afferent neurons involved inthe signaling pathway that leads to the sensation of pain. TRPV1 isactivated by a diverse range of stimuli, including vanilloids, membranedepolarization, heat, stretch, low pH, inflammatory mediators (e.g.,lipoxygenase metabolites), and endocannabinoid compounds. Becauseheightened activity of nociceptors contributes to unwanted pain,inflammatory conditions, thermoregulation, and control of smooth muscletone and reflexes in mammals, modulation of signaling in this pathway isimportant in treatment and prophylaxis of various clinical syndromes(Caterina, M. J., Pain 2003, 105(1-2), 5-9; Caterina, M. J. et. al.,Annu. Rev. Neurosci. 2001, 24, 487-517; Tominaga, M. et. al., J.Neurobiol. 2004, 61, 3-12; Voets, T. et. al., Nature 2004, 430,748-754).

Because of TRPV1's connection with the sensory nervous system, TRPV1agonists and antagonists may be therapeutically useful in the treatmentor prophylaxis of disease states, disorders, and conditions mediated byTRPV1 activity, such as: i) pain (e.g., acute, chronic, inflammatory, orneuropathic pain); ii) itch (Kim et al., Neurosci. Lett. 2004, 361, 159)and various inflammatory disorders (Stucky, C. L. et. al., Neuroscience1998, 84, 1257; Moore, B. A. et. al., Am. J. Physiol. Gastrointest.Liver Physiol. 2002, 282, G1045; Kwak, J. Y. et. al., Neuroscience 1998,86, 619; Morris, V. H. et. al., Pain 1997, 71, 179; Greiff, L. et. al.,Thorax 1995, 50, 225); iii) inner ear disorders (Balaban, C. D. et al.,Hear. Res. 2003, 175, 165-70; Zheng, J. et al., J. Neurophys. 2003, 90,444-55); iv) fever and other disorders or symptoms affected bythermoregulation (Jancso-Gabor et al., J. Physiol. 1970, 206, 495;Swanson et al., J. Med. Chem. 48, 1857; Iida et al., Neurosci. Lett.2005, 378, 28); v) tracheobronchial and diaphragmatic dysfunction; andvi) gastrointestinal and urinary tract disorders (Lazzeri, M. et al.,Eur. Urology 200, 792-798; Apostolidis, A. et. al., Urology 2005, 65,400-405). Additionally, TRPV1 modulators may be therapeutically usefulin the treatment or prophylaxis of anxiety (Marsch, R. et al., J.Neurosci. 2007, 27(4), 832-839); eye-related disorders (such asglaucoma, vision loss, and increased intraocular pressure) (Calkins, D.J. et al., Abstract from ARVO 2006 Annual Meeting, Program #1557, Poster#B93); baldness (e.g., by stimulating hair growth) (Bodo, E. et al., Am.J. Pathol. 2005, 166(4), 985-998); diabetes (including insulin-resistantdiabetes or diabetic conditions mediated by insulin sensitivity orsecretion) (Razavi, R. et al., Cell 2006, 127(6), 1097-1099; Akiba, Y.et al., Biochem. Biophy. Res. Commun. 2004, 321(1), 219-225).

Acidosis is a well-established feature of cerebral ischaemia. Tissue pHmay fall to 6 or lower, sufficient to activate TRPV1 channels expressedin the CNS. TRPV1 antagonists therefore may be useful in the treatmentof disorders associated with reduced blood flow to the CNS or CNShypoxia, such as head trauma, spinal injury, thromboembolic orhemorrhagic stroke, transient ischaemic attacks, cerebral vasospasm,hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia,Alzheimer's disease, and Huntington's Disease.

International Publication No. WO05/014558 (Feb. 17, 2005) describescertain aminopyrimidine inhibitors of voltage-gated sodium and potassiumchannel. Various bicyclic pyrimidines are disclosed as serotoninreceptor modulators in U.S. patent application Ser. No. 11/460,294,filed Jul. 27, 2006. Condensed pyrimidine compounds are disclosed asinhibitors of voltage-gated ion channels in Intl. Publication No. WO05/014558. Various bicyclic pyrimidines are also disclosed in Intl.Publication No. WO 05/066171 and U.S. Patent Appl. Publ. 2005/0165032 asinhibitors of the TRPV1 channel. However, there remains a need forpotent TRPV1 modulators with desirable pharmaceutical properties.

SUMMARY OF THE INVENTION

Certain tetrahydro-pyrimidoazepine derivatives have now been found tohave TRPV1-modulating activity. Thus, the invention is directed to thegeneral and preferred embodiments defined, respectively, by theindependent and dependent claims appended hereto, which are incorporatedby reference herein.

Thus, in one general aspect the invention relates to compounds of thefollowing Formula (I):

wherein:

-   R¹ is —H; —NR^(a)R^(b); —OH; a —C₁₋₆alkyl, —OC₁₋₆alkyl,    —O-(saturated monocyclic cycloalkyl), —OC₁alkyl-(saturated    monocyclic cycloalkyl), —O-(saturated monocyclic heterocycloalkyl),    —O-phenyl, —O-benzyl, —S—C₁₋₆alkyl, —S-(saturated monocyclic    cycloalkyl), —SC₁alkyl-(saturated monocyclic cycloalkyl),    —S-(saturated monocyclic heterocycloalkyl), —S-phenyl, —S-benzyl, or    —SO₂—C₁₋₆alkyl group unsubstituted or substituted with one or two    moieties independently selected from the group consisting of    —C₁₋₆alkyl, —OH, —OC₁₋₄alkyl, —NR^(e)R^(f), and halo substituents;    or a phenyl, monocyclic cycloalkyl, or monocyclic heteroaryl group    unsubstituted or substituted with a —C₁₋₆alkyl, —OH, —OC₁₋₄alkyl,    —NR^(e)R^(f), or halo substituent;    -   where R^(a) and R^(b) are each independently —H; —C₁₋₆alkyl; a        —C₂₋₃alkyl group substituted with a —OH, —OC₁₋₄alkyl,        —NR^(c)R^(d), or halo substituent; or a saturated monocyclic        cycloalkyl, —C₁alkyl-(saturated monocyclic cycloalkyl),        saturated monocyclic heterocycloalkyl, —C₁alkyl-(saturated        monocyclic heterocycloalkyl), phenyl, benzyl, or        —C₁alkyl-(monocyclic heteroaryl) group unsubstituted or        substituted with one, two, or three moieties independently        selected from the group consisting of —C₁₋₆alkyl, —OH,        —OC₁₋₄alkyl, —NR^(p)R^(q), and halo substituents; or        -   R^(a) and R^(b) taken together with their nitrogen of            attachment form a saturated monocyclic heterocycloalkyl or            bridged bicyclic heterocycloalkyl group unsubstituted or            substituted with one, two, or three moieties independently            selected from the group consisting of —C₁₋₆alkyl,            —C₁₋₄alkyl-OH, —C₁₋₂alkyl-OC₁₋₂alkyl, —OH, —OC₁₋₄alkyl,            —NR^(p)R^(q), halo, —CO₂H, and benzyl substituents;        -   where R^(c) and R^(d) are each independently —H or            —C₁₋₆alkyl; or R^(c) and R^(d) taken together with their            nitrogen of attachment form a saturated monocyclic            heterocycloalkyl;        -   where R^(p) and R^(q) are each independently —H or            —C₁₋₆alkyl; or R^(p) and R^(q) taken together with their            nitrogen of attachment form a saturated monocyclic            heterocycloalkyl;        -   where R^(e) and R^(f) are each independently —H or            —C₁₋₆alkyl; or R^(e) and R^(f) taken together with their            nitrogen of attachment form a saturated monocyclic            heterocycloalkyl;-   R² is —H or —C₁₋₆alkyl;-   R³ is a monocyclic cycloalkyl, phenyl, benzyl, phenethyl, indanyl,    thiazolyl, thiophenyl, pyridyl, pyridylmethyl, pyrimidinyl,    pyrazinyl, pyridazinyl, benzothiadiazolyl, quinolinyl,    isoquinolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl    group unsubstituted or substituted with one, two, or three R^(g)    substituents;    -   where each R^(g) substituent is —C₁₋₆alkyl; —C₁₋₄alkyl-OH        unsubstituted or substituted with —CF₃; saturated monocyclic        cycloalkyl; —OH; —OC₁₋₆alkyl; phenoxy; —CN; —NO₂;        —N(R^(h))R^(i); —C₁₋₄alkyl-N(R^(h))R^(i); —C(O)N(R^(h))R^(i);        —N(R^(h))C(O)R^(i); —N(R^(h))SO₂C₁₋₆alkyl; —C(O)C₁₋₆alkyl;        —S(O)₀₋₂—C₁₋₆alkyl; —SO₂CF₃; —SO₂N(R^(h))R^(i); —SCF₃; halo;        —CF₃; —OCF₃; —CO₂H; —CO₂C₁₋₆alkyl; —C(R^(j))(R^(x))—CN;        —C(R^(j))(R^(x))—OH; —C(R^(j))(R^(x))—CO₂C₁₋₆alkyl;        —C(R^(j))(R^(x))—CO₂H; —C(R^(j))(R^(x))—C(O)N(R^(h))R^(i);        phenyl; or monocyclic heteroaryl; or        -   two adjacent R^(g) substituents taken together form            —OC₁₋₂alkylO—;        -   where R^(h) and R^(i) are each independently —H or            —C₁₋₆alkyl; or R^(h) and R^(i) (when both are present) taken            together with their nitrogen of attachment form a saturated            monocyclic heterocycloalkyl group;        -   R^(j) is independently —H, —C₁₋₆alkyl, or —CF₃;        -   R^(x) is —H or —C₁₋₆alkyl; or R^(j) and R^(x) taken together            with the carbon to which they are attached form a monocyclic            cycloalkyl ring;-   and-   Ar is a phenyl, pyridyl, imidazolyl, pyrimidinyl, pyridazinyl, or    fused-bicyclic heteroaryl group unsubstituted or substituted with    one, two, or three R^(k) substituents;    -   where each R^(k) substituent is independently —C₁₋₆alkyl,        —C₁₋₂alkyl-OH, —OH, —OC₁₋₆alkyl, phenoxy, —CN, —NO₂,        —N(R^(l))R^(m), —C(O)N(R^(l))R^(m), —N(R^(l))C(O)R^(m),        —N(R^(l))SO₂C₁₋₆alkyl, —N(R^(l))SO₂CF₃, —C(O)C₁₋₆alkyl,        —S(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SO₂N(R^(l))R^(m), —SCF₃, halo,        —CF₃, —OCF₃, —CO₂H, or —CO₂C₁₋₆alkyl; or        -   two adjacent R^(k) substituents taken together form            —OC₁₋₂alkylO—;        -   where R^(l) and R^(m) are each independently —H, —C₁₋₆alkyl,            saturated monocyclic cycloalkyl, or —CF₃.

The invention also relates to pharmaceutically acceptable salts,pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites of compounds of Formula (I). In certain preferredembodiments, the compound of Formula (I) is a compound selected fromthose species described or exemplified in the detailed descriptionbelow.

In a further general aspect, the invention relates to pharmaceuticalcompositions each comprising: (a) an effective amount of an agentselected from compounds of Formula (I) and pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites thereof; and (b) a pharmaceutically acceptable excipient.

In another general aspect, the invention is directed to a method oftreating a subject suffering from or diagnosed with a disease, disorder,or medical condition mediated by TRPV1 activity, comprisingadministering to the subject in need of such treatment an effectiveamount of a compound of Formula (I), or a pharmaceutically acceptablesalt, pharmaceutically acceptable prodrug, or pharmaceutically activemetabolite of such compound. In certain preferred embodiments of theinventive method, the disease, disorder, or medical condition isselected from: pain (acute, chronic, inflammatory, or neuropathic pain);itch or various inflammatory disorders; inner ear disorders; fever andother conditions or disorders of thermoregulation; tracheobronchial anddiaphragmatic dysfunction; gastrointestinal and urinary tract disorders;and disorders associated with reduced blood flow to the CNS or CNShypoxia.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION OF INVENTION AND ITS PREFERRED EMBODIMENTS

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Exemplary alkyl groupsinclude methyl (Me, which also may be structurally depicted bya/symbol), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, andthe like.

The term “alkenyl” refers to a straight- or branched-chain alkenyl grouphaving from 2 to 12 carbon atoms in the chain. (The double bond of thealkenyl group is formed by two sp² hybridized carbon atoms.)Illustrative alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl,2-methylprop-2-enyl, hex-2-enyl, and the like.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or bridged polycyclic carbocycle havingfrom 3 to 12 ring atoms per carbocycle. Illustrative examples ofcycloalkyl groups include the following moieties:

and the like.

A “heterocycloalkyl” refers to a monocyclic, or fused, bridged, or spiropolycyclic ring structure that is saturated or partially saturated andhas from 3 to 12 ring atoms per ring structure selected from carbonatoms and up to three heteroatoms selected from nitrogen, oxygen, andsulfur. The ring structure may optionally contain up to two oxo groupson carbon or sulfur ring members. Illustrative examples ofheterocycloalkyl groups include:

and the like.

The term “heteroaryl” refers to a monocyclic, fused bicyclic, or fusedpolycyclic aromatic heterocycle (ring structure having ring atomsselected from carbon atoms and up to four heteroatoms selected fromnitrogen, oxygen, and sulfur) having from 3 to 12 ring atoms perheterocycle. Illustrative examples of heteroaryl groups include thefollowing moieties:

and the like.

Those skilled in the art will recognize that the species of cycloalkyl,heterocycloalkyl, and heteroaryl groups listed or illustrated above arenot exhaustive, and that additional species within the scope of thesedefined terms may also be selected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof.

Furthermore, certain structures may exist as geometric isomers (i.e.,cis and trans isomers), as tautomers, or as atropisomers. Additionally,any formula given herein is intended to embrace hydrates, solvates, andpolymorphs of such compounds, and mixtures thereof.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl,¹²⁵I, respectively. Such isotopically labeled compounds are useful inmetabolic studies (preferably with ¹⁴C), reaction kinetic studies (with,for example ²H or ³H), detection or imaging techniques [such as positronemission tomography (PET) or single-photon emission computed tomography(SPECT)] including drug or substrate tissue distribution assays, or inradioactive treatment of patients. In particular, an ¹⁸F or ¹¹C labeledcompound may be particularly preferred for PET or SPECT studies.Further, substitution with heavier isotopes such as deuterium (i.e., ²H)may afford certain therapeutic advantages resulting from greatermetabolic stability, for example increased in vivo half-life or reduceddosage requirements. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the moiety for the variable appearingelsewhere. In other words, where a variable appears more than once, thechoice of the species from a specified list is independent of the choiceof the species for the same variable elsewhere in the formula.

In preferred embodiments of agents of Formula (I), R¹ is —H or —OH. Infurther preferred embodiments, R¹ is isopropyl or cyclopropyl. Infurther preferred embodiments, R¹ is a —O-(saturated monocycliccycloalkyl), —OC₁alkyl-(saturated monocyclic cycloalkyl), —O-(saturatedmonocyclic heterocycloalkyl), —O-phenyl, or —O-benzyl groupunsubstituted or substituted with one or two moieties independentlyselected from the group consisting of methyl, ethyl, and isopropylsubstituents. In further preferred embodiments, R¹ is a —S—C₁₋₆alkyl,—S-(saturated monocyclic cycloalkyl), —SC₁alkyl-(saturated monocycliccycloalkyl), —S-(saturated monocyclic heterocycloalkyl), —S-phenyl, or—S-benzyl group unsubstituted or substituted with a methyl, ethyl, orisopropyl substituent. In further preferred embodiments, R¹ ismethylsulfanyl or methylsulfonyl. In further preferred embodiments, R¹is a monocyclic heteroaryl group unsubstituted or substituted with amethyl substituent. In further preferred embodiments, R¹ is a furanyl,thiophenyl, thiazolyl, or pyridyl group unsubstituted or substitutedwith a methyl substituent.

In preferred embodiments, R^(a) and R^(b) are each independently —H;methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, or hexyl; an ethyl or propyl groupsubstituted with an —OC₁₋₄alkyl or —NR^(c)R^(d) substituent; or acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, aziridinyl,pyrrolidinyl, tetrahydrofuranyl, piperidinyl, tetrahydropyranyl,piperazinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, phenyl, or furanylmethyl groupunsubstituted or substituted with a methyl or methoxy substituent. Infurther preferred embodiments, R^(a) and R^(b) are each independently—H, methyl, isopropyl, methoxyethyl, cyclopropyl, cyclohexyl,cyclopropylmethyl, 2-piperidin-1-yl-ethyl, or 2-dimethylamino-ethyl. Infurther preferred embodiments, R^(a) and R^(b) taken together with theirnitrogen of attachment form an aziridinyl, pyrrolidinyl, piperidinyl,2-oxo-piperidin-1-yl, piperazinyl, oxo-piperazinyl, morpholinyl,thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholin-4-yl,1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl, azepanyl, 1,4-oxazepanyl, or7-azabicyclo[2.2.1]hept-7-yl group unsubstituted or substituted with a—C₁₋₆alkyl, hydroxymethyl, hydroxyethyl, methoxymethyl, methoxyethyl,fluoro, —OH, or —CO₂H substituent.

In preferred embodiments, R^(c) and R^(d) taken together with theirnitrogen of attachment form piperidinyl, morpholinyl, or pyrrolidinyl.

In preferred embodiments, R³ is a monocyclic cycloalkyl, pyridylmethyl,benzothiadiazolyl, tetrahydroquinolinyl, or tetrahydroisoquinolinylgroup unsubstituted or substituted with one, two, or three R^(g)substituents. In further preferred embodiments, R³ is a 2-pyridyl groupunsubstituted or substituted with one or two R^(g) substituents. Infurther preferred embodiments, R³ is a 2-pyridyl group unsubstituted orsubstituted with one or two R^(g) substituents. In further preferredembodiments, R³ is a 3-pyridyl group unsubstituted or substituted withone R^(g) substituent.

In preferred embodiments, each R^(g) substituent is independentlymethyl, isopropyl, tert-butyl, —CF₃, fluoro, chloro, bromo, —OCF₃,—SO₂NH₂, —OCH₃, phenoxy, —C(CH₃)₂—CN, —C(CH₃)₂—OH, —NO₂, —CN, —NH₂,—C(O)CH₃, —SO₂CF₃, —SCF₃, —CON(CH₃)₂, —CO₂H, phenyl, cyclohexyl,pyrrolidinyl, piperidinyl, morpholinyl, —SCH₃, oxazolyl,—SO₂-(pyrrolidinyl), —SO₂N(CH₃)₂, —C(CH₃)₂—CO₂CH₃, —C(CH₃)₂—CO₂H,1-hydroxy-ethyl, 2-hydroxy-1,1-dimethyl-ethyl,3,3,3-trifluoro-1-hydroxy-propyl,3,3,3-trifluoro-1-hydroxy-1-methyl-propyl, or —SO₂CH₃; or two adjacentR^(g) substituents taken together form —OC₁₋₂alkylO—. In furtherpreferred embodiments, each R^(g) substituent is independently methyl,isopropyl, tert-butyl, fluoro, —CF₃, chloro, —C(CH₃)₂—CN, —C(CH₃)₂—OH,—C(CH₃)₂—CH₂OH, —C(CH₃)₂—CO₂H, acetyl, —SO₂CH₃, or —SO₂CF₃.

In preferred embodiments, R^(h) and R^(i) taken together with theirnitrogen of attachment form pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl.

In preferred embodiments, R^(j) is —H, methyl, or —CF₃. In preferredembodiments, R^(x) is —H or methyl. In further preferred embodiments,R^(j) and R^(x) taken together with the carbon to which they areattached form a cyclopropyl ring.

In preferred embodiments, Ar is 2-pyridyl substituted with —CF₃. Infurther preferred embodiments, Ar is 2-pyridyl substituted with —Cl,—Br, —F, methyl, —SO₂CH₃, or —SO₂CH₂CH₃. In further preferredembodiments, Ar is 2-pyridyl, substituted with one or two R^(k)substituents independently selected from the group consisting of: —CF₃,fluoro, chloro, bromo, —SO₂CH₃, —NH₂, —NO₂, —CO₂CH₃, —NHSO₂CH₃, —CN,—CONH₂, —SO₂CH₂CH₃, —SO₂NH₂, —SO₂NH-cyclopropyl, —SO₂NH-isopropyl,—CO₂H, —CH₂OH, and methyl.

In preferred embodiments, R^(l) and R^(m) are each independently —H,methyl, ethyl, isopropyl, —CF₃, or cyclopropyl.

In preferred embodiments, R¹ is —H. In other preferred embodiments, R¹is —NR^(a)R^(b), and R^(a) and R^(b) are as previously defined. Infurther preferred embodiments, R¹ is a —C₁₋₆alkyl group unsubstituted orsubstituted with a —OH, —OC₁₋₄alkyl, —NR^(e)R^(f), or halo substituent,and R^(e) and R^(f) are as previously defined. In further preferredembodiments, R¹ is methyl or isopropyl. In still further preferredembodiments, R¹ is a methyl group substituted with a —OC₁₋₄alkyl or—NR^(e)R^(f) substituent, and R^(e) and R^(f) are as previously defined.In further preferred embodiments, R¹ is methoxymethyl orpiperidinylmethyl. In other preferred embodiments, R¹ is methoxy,methylsulfanyl, or methylsulfonyl. In additional preferred embodiments,R¹ is cyclopropyl.

In preferred embodiments, R^(a) and R^(b) are each independently —H;methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, or hexyl; an ethyl or propyl groupsubstituted with an —OC₁₋₄alkyl or —NR^(c)R^(d) substituent; or acyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclopropylmethyl, cyclopentylmethyl, aziridinyl, pyrrolidinyl,tetrahydrofuranyl, piperidinyl, tetrahydropyranyl, piperazinyl,morpholinyl, thiomorpholinyl, 1,1-dioxo-1λ⁶-thiomorpholin-4-yl, orphenyl group unsubstituted or substituted with a —C₁₋₆alkyl,—OC₁₋₄alkyl, or halo substituent; and R^(c) and R^(d) are as previouslydefined. In other preferred embodiments, R^(a) and R^(b) are eachindependently —H, methyl, methoxyethyl, cyclopropyl, cyclopropylmethyl,2-piperidin-1-yl-ethyl, or 2-dimethylamino-ethyl. Alternatively, R^(a)and R^(b) taken together with their nitrogen of attachment form anaziridinyl, pyrrolidinyl, piperidinyl, 2-oxo-piperidin-1-yl,piperazinyl, oxo-piperazinyl, morpholinyl, thiomorpholinyl,1,1-dioxo-1λ⁶-thiomorpholin-4-yl, 1,1-dioxo-1λ⁶-[1,2]thiazinan-2-yl, orazepanyl group unsubstituted or substituted with a —C₁₋₆alkyl, —OH, or—CO₂H substituent.

In preferred embodiments, R^(c) and R^(d) are each independently —H,methyl, or ethyl. Alternatively, R^(c) and R^(d) taken together withtheir nitrogen of attachment form piperidinyl.

In preferred embodiments, R^(p) and R^(q) are each independently —H,methyl, or ethyl.

In preferred embodiments, R^(e) and R^(f) are each independently —H,methyl, or ethyl.

Preferably, R² is —H or methyl; more preferably, R² is —H.

Preferably, R³ is a phenyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl,or isoquinolinyl group unsubstituted or substituted with one or twoR^(g) substituents, and each R^(g) substituent is as previously defined.In further preferred embodiments, R³ is a pyridyl, pyrimidinyl,pyrazinyl, quinolinyl, or isoquinolinyl group unsubstituted orsubstituted with one or two R^(g) substituents, and each R^(g)substituent is as previously defined. In additional preferredembodiments, R³ is a pyridyl, thiazolyl, or pyridazinyl groupunsubstituted or substituted with one or two R^(g) substituents, andeach R^(g) substituent is as previously defined. In still furtherpreferred embodiments, R³ is a phenyl group substituted with one or twoR^(g) substituents, and each R^(g) substituent is as previously defined.In still further preferred embodiments, R³ is a benzyl or phenethylgroup unsubstituted or substituted with one or two R^(g) substituents,and each R^(g) substituent is as previously defined. In still furtherpreferred embodiments, R³ is a 2-pyridyl group unsubstituted orsubstituted with one R^(g) substituent, and R^(g) substituent is aspreviously defined.

Preferably, each R^(g) substituent is —C₁₋₆alkyl, —OH, —OC₁₋₆alkyl,phenoxy, —CN, —NO₂, —N(R^(h))R^(i), —C(O)N(R^(h))R^(i),—N(R^(h))C(O)R^(i), —N(R^(h))SO₂C₁₋₆alkyl, —C(O)C₁₋₆alkyl,—S(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SO₂N(R^(h))R^(i), —SCF₃, halo, —CO₂H,—CO₂C₁₋₆alkyl, —C(R^(j))₂—CN, or —C(R^(j))₂—OH, and R^(h), R^(i), andR^(j) are as previously defined. Alternatively, two adjacent R^(g)moieties taken together form —OC₁₋₂alkylO—. In further preferredembodiments, each R^(g) substituent is isopropyl, tert-butyl, —CF₃,chloro, —OCF₃, —SO₂NH₂, —OCH₃, phenoxy, bromo, —C(CH₃)₂—CN, —C(CH₃)₂—OH,—NO₂, —CN, —NH₂, —C(O)CH₃, —SO₂CF₃, or —SCF₃; or two adjacent R^(g)substituents taken together form —OC₁₋₂alkylO—. In still furtherpreferred embodiments, each R^(g) substituent is isopropyl, tert-butyl,—CF₃, chloro, —C(CH₃)₂—CN, —C(CH₃)₂—OH, or —SO₂CF₃.

In preferred embodiments, R^(h) and R^(i) are each independently —H,methyl, or ethyl.

In preferred embodiments, R^(j) is —H, methyl, or ethyl.

In preferred embodiments, Ar is a phenyl group unsubstituted orsubstituted with one or two R^(k) substituents, and each R^(k)substituent is as previously defined. In further preferred embodiments,Ar is a phenyl group substituted with a —NO₂, —N(R^(l))R^(m),—C(O)N(R^(l))R^(m), —N(R^(l))C(O)R^(m), —N(R^(l))SO₂C₁₋₆alkyl,—N(R^(l))SO₂CF₃, —SO₂CH₃, or —SO₂CF₃ substituent, and R^(l) and R^(m)are as previously defined. In still further preferred embodiments, Ar isa fused-bicyclic heteroaryl group unsubstituted or substituted with oneor two R^(k) substituents, and each R^(k) substituent is as previouslydefined. In still further preferred embodiments, Ar is 2-pyridylsubstituted with —CF₃, —NO₂, or —N(R^(l))R^(m), and R^(l) and R^(m) areas previously defined. In still further preferred embodiments, Ar is2-pyridyl substituted with —Cl, —Br, methyl, or —SO₂CH₃. In stillfurther preferred embodiments, Ar is quinoxalinyl or phthalizinyl. Instill further preferred embodiments, Ar is a phenyl, pyridyl,pyrimidinyl, or fused-bicyclic heteroaryl group substituted on a carbonring atom at a position ortho to the point of attachment with an R^(k)substituent, and the R^(k) substituent is as previously defined.

In preferred embodiments, each R^(k) substituent is —C₂₋₆alkyl, —OH,phenoxy, —CN, —NO₂, —N(R^(l))R^(m), —C(O)N(R^(l))R^(m),—N(R^(l))C(O)R^(m), —N(R^(l))SO₂C₁₋₆alkyl, —N(R^(l))SO₂CF₃,—C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SO₂N(R^(l))R^(m), —SCF₃,—OCF₃, —CO₂H, or —CO₂C₁₋₆alkyl; or two adjacent R^(k) substituents takentogether form —OC₁₋₂alkylO—; and R^(l) and R^(m) are as previouslydefined. In still further preferred embodiments, each R^(k) substituentis —N(R^(l))R^(m), —NO₂, —N(R^(l))SO₂CF₃, or —N(R^(l))SO₂CH₃, and R^(l)and R^(m) are as previously defined.

In preferred embodiments, R^(l) and R^(m) are each independently —H,methyl, ethyl, or —CF₃.

Further preferred embodiments of the present invention include compoundsof Formula (I) wherein:

a) R¹ is —H, —NR^(a)R^(b), —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—SO₂—C₁₋₆alkyl, —CH₂—O—C₁₋₄alkyl, or —CH₂—NR^(e)R^(f); R² is —H; R³ is apyridyl, pyrimidinyl, pyrazinyl, quinolinyl, or isoquinolinyl groupunsubstituted or substituted with one or two R^(g) substituents; and Aris a phenyl group substituted with one or two R^(k) substituents; andR^(a), R^(b), R^(e), R^(f), R^(g), and R^(k) are as previously defined;or

b) R¹ is —H, —NR^(a)R^(b), —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—SO₂—C₁₋₆alkyl, —CH₂—O—C₁₋₄alkyl, or —CH₂—NR^(e)R^(f); R² is —H; R³ is abenzyl, phenethyl, indanyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl,or isoquinolinyl group unsubstituted or substituted with one or twoR^(g) substituents; and Ar is a phenyl group substituted with one or twoR^(k) substituents, where each R^(k) substituent is —C₂₋₆alkyl, —OH,phenoxy, —CN, —NO₂, —N(R^(l))R^(m), —C(O)N(R^(l))R^(m),—N(R^(l))C(O)R^(m), —N(R^(l))SO₂C₁₋₆alkyl, —N(R^(l))SO₂CF₃,—C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SO₂N(R^(l))R^(m), —SCF₃,—OCF₃, —CO₂H, or —CO₂C₁₋₆alkyl; or two adjacent R^(k) substituents takentogether form —OC₁₋₂alkylO—; and R^(a), R^(b), R^(e), R^(f), R^(g),R^(l), and R^(m) are as previously defined; or

c) R¹ is —H, —NR^(a)R^(b), —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—SO₂—C₁₋₆alkyl, —CH₂—O—C₁₋₄alkyl, or —CH₂—NR^(e)R^(f); R² is —H; R³ is abenzyl or phenethyl group unsubstituted or substituted with one or twoR^(g) substituents; and Ar is 2-pyridyl substituted with —CF₃, —NO₂, or—N(R^(l))R^(m); and R^(a), R^(b), R^(e), R^(f), R^(g), R^(l), and R^(m)are as previously defined; or

d) R¹ is —C₁₋₆alkyl; R² is —H; R³ is a phenyl, pyridyl, pyrimidinyl,pyrazinyl, quinolinyl, or isoquinolinyl group unsubstituted orsubstituted with one or two R^(g) substituents; and Ar is a phenyl,pyridyl, pyrimidinyl, or fused-bicyclic heteroaryl group unsubstitutedor substituted with one or two R^(k) substituents; and R^(g) and R^(k)are as previously defined; or

e) R¹ is —H, —NR^(a)R^(b), —C₁₋₆alkyl, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—SO₂—C₁₋₆alkyl, —CH₂—O—C₁₋₄alkyl, or —CH₂—NR^(e)R^(f); R² is —H; R³ is aphenyl, benzyl, phenethyl, indanyl, pyridyl, pyrimidinyl, pyrazinyl,quinolinyl, or isoquinolinyl group unsubstituted or substituted with oneor two R^(g) substituents; and Ar is a fused-bicyclic heteroaryl groupunsubstituted or substituted with one or two R^(k) substituents; andR^(a), R^(b), R^(e), R^(f), R^(g), and R^(k) are as previously defined;or

f) R¹ is —NR^(a)R^(b); R² is —H; R³ is a phenyl group substituted withone or two R^(g) substituents, where each R^(g) substituent is—C₁₋₆alkyl, —OH, —OC₁₋₆alkyl, phenoxy, —CN, —NO₂, —N(R^(h))R^(i),—C(O)N(R^(h))R^(i), —N(R^(h))C(O)R^(i), —N(R^(h))SO₂C₁₋₆alkyl,—C(O)C₁₋₆alkyl, —S(O)₀₋₂—C₁₋₆alkyl, —SO₂CF₃, —SO₂N(R^(h))R^(i), —SCF₃,halo, —CO₂H, —CO₂C₁₋₆alkyl, —C(R^(j))₂—CN, or —C(R^(j))₂—OH; or twoadjacent R^(g) substituents taken together form —OC₁₋₂alkylO—; and Ar isa phenyl, pyridyl, pyrimidinyl, or fused-bicyclic heteroaryl groupunsubstituted or substituted with one or two R^(k) substituents; andR^(a), R^(b), R^(h), R^(i), R^(j), and R^(k) are as previously defined;or

g) R¹ is —NR^(a)R^(b); R² is —H; R³ is a phenyl, benzyl, phenethyl,indanyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, or isoquinolinylgroup unsubstituted or substituted with one or two R^(g) substituents;and Ar is a phenyl group unsubstituted or substituted with one or twoR^(k) substituents; and R^(a), R^(b), R^(g), and R^(k) are as previouslydefined.

The invention includes also pharmaceutically acceptable salts of thecompounds represented by Formula (I), preferably of those describedabove. Pharmaceutically acceptable salts of the specific compoundsexemplified herein are especially preferred.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, S. M. Berge et al.,“Pharmaceutical Salts”, J. Pharm. Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Preferred pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. A compound of Formula (I)may possess a sufficiently acidic group, a sufficiently basic group, orboth types of functional groups, and accordingly react with a number ofinorganic or organic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. Exemplary pharmaceutically acceptablesalts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites,phosphates, monohydrogen-phosphates, dihydrogenphosphates,metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, γ-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, and mandelates.

If the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, or ethanesulfonic acid, or the like.

If the compound of Formula (I) is an acid, such as a carboxylic acid orsulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, or alkaline earth metalhydroxide, or the like. Illustrative examples of suitable salts includeorganic salts derived from amino acids, such as glycine and arginine,ammonia, carbonates, bicarbonates, primary, secondary, and tertiaryamines, and cyclic amines, such as benzylamines, pyrrolidines,piperidine, morpholine, and piperazine, and inorganic salts derived fromsodium, calcium, potassium, magnesium, manganese, iron, copper, zinc,aluminum, and lithium.

In preferred embodiments, the present invention relates to compounds ofFormula (I) and to sulfate, hydrochloride, fumarate, tartrate,phosphate, methanesulfonic acid (mesylate), benzenesulfonic acid(besylate), and p-toluensulfonic acid (tosylate) salts thereof.

The invention also relates to treatment methods employingpharmaceutically acceptable prodrugs of the compounds of Formula (I).The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula(I)). A “pharmaceutically acceptable prodrug” is a prodrug that is nottoxic, biologically intolerable, or otherwise biologically unsuitablefor administration to the subject. Illustrative procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Exemplary amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Preferred amides are derived from ammonia, C₁₋₃alkyl primaryamines, and di(C₁₋₂alkyl)amines. Exemplary esters of the inventioninclude C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆alkyl) esters.Preferred esters include methyl esters. Prodrugs may also be prepared byderivatizing free hydroxy groups using groups including hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, following procedures such as thoseoutlined in Adv. Drug Delivery Rev. 1996, 19, 115. Carbamate derivativesof hydroxy and amino groups may also yield prodrugs. Carbonatederivatives, sulfonate esters, and sulfate esters of hydroxy groups mayalso provide prodrugs. Derivatization of hydroxy groups as(acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acyl group may bean alkyl ester, optionally substituted with one or more ether, amine, orcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, is also useful to yield prodrugs.Prodrugs of this type may be prepared as described in J. Med. Chem.1996, 39, 10. Free amines can also be derivatized as amides,sulfonamides or phosphonamides. All of these prodrug moieties mayincorporate groups including ether, amine, and carboxylic acidfunctionalities.

Pharmaceutically active metabolites may also be used in the methods ofthe invention. A “pharmaceutically active metabolite” means apharmacologically active product of metabolism in the body of a compoundof Formula (I) or salt thereof. Prodrugs and active metabolites of acompound may be determined using routine techniques known or availablein the art. See, e.g., Bertolini et al., J. Med. Chem. 1997, 40,2011-2016; Shan et al., J. Pharm. Sci. 1997, 86 (7), 765-767; Bagshawe,Drug Dev. Res. 1995, 34, 220-230; Bodor, Adv. Drug Res. 1984, 13,224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); andLarsen, Design and Application of Prodrugs, Drug Design and Development(Krogsgaard-Larsen et al., eds., Harwood Academic Publishers, 1991).

The compounds of Formula (I) and their pharmaceutically acceptablesalts, pharmaceutically acceptable prodrugs, and pharmaceutically activemetabolites (collectively, “agents”) of the present invention are usefulas TRPV1 modulators in the methods of the invention. The agents may beused in the inventive methods for the treatment or prevention of medicalconditions, diseases, or disorders mediated through modulation of TRPV1,such as those described herein. Symptoms or disease states are intendedto be included within the scope of “medical conditions, disorders, ordiseases.”

Accordingly, the invention relates to methods of using thepharmaceutical agents described herein to treat subjects diagnosed withor suffering from a disease, disorder, or condition mediated throughTRPV1 activity, such as: i) pain (acute, chronic, inflammatory, orneuropathic pain); ii) itch or various inflammatory disorders; iii)inner ear disorders; iv) fever and other disorders of thermoregulation;v) tracheobronchial and diaphragmatic dysfunction; vi) gastrointestinaland urinary tract disorders; and vii) disorders associated with reducedblood flow to the CNS or CNS hypoxia.

In a preferred embodiment, an agent of the present invention isadministered to treat pain. Pain may be associated with variousdiseases, disorders, or conditions, and may include various etiologies.Exemplary types of pain treatable with a TRPV1-modulating agentaccording to the invention include pain arising from or caused by:osteoarthritis, rotator cuff disorders, arthritis (e.g., rheumatoidarthritis or inflammatory arthritis), fibromyalgia, migraine andheadache (e.g. cluster headache, sinus headache, or tension headache;see, Goadsby Curr. Pain Headache Reports 2004, 8, 393), sinusitis, oralmucositis, toothache, dental trauma, dental extractions, dentalinfections, burn, sunburn, dermatitis, psoriasis, eczema, insect stingor bite, burn pain (Bolkskei et al., Pain 2005, in press),musculoskeletal disorders, bony fractures, ligamentous sprains, plantarfasciitis, costochondritis, tendonitis, bursitis, tennis elbow,pitcher's elbow, patellar tendonitis, repetitive strain injury,myofascial syndrome, muscle strain, myositis, temporomandibular jointdisorder, amputation, low back pain, spinal cord injury, neck pain,whiplash, bladder spasms, GI tract disorders, interstitial cystitis,urinary tract infection, urethral colic, renal colic, pharyngitis, coldsores, stomatitis, external otitis, otitis media (Chan et al., Lancet2003, 361, 385), burning mouth syndrome, mucositis, esophageal pain,esophageal spasms, abdominal disorders, gastroesophageal reflux disease,pancreatitis, enteritis, irritable bowel disorder, inflammatory boweldisease, Crohn's disease, ulcerative colitis, colon distension,abdominal constriction, diverticulosis, diverticulitis, intestinal gas,hemorrhoids, anal fissures, anorectal disorders, prostatitis,epididymitis, testicular pain, proctitis, rectal pain, cholecystitis,labor, childbirth, endometriosis, menstrual cramps, pelvic pain,vulvodynia, vaginitis, orolabial and genital infections (e.g. herpessimplex), pleurisy, pericarditis, non-cardiac chest pain, contusions,abrasions, skin incision (Honore, P. et al., J. Pharmacol. Exp. Ther.2005, 314, 410-21), postoperative pain, peripheral neuropathy, centralneuropathy, diabetic neuropathy, acute herpetic neuralgia, post-herpeticneuralgia, trigeminal neuralgia, glossopharyngeal neuralgia, atypicalfacial pain, gradiculopathy, HIV associated neuropathy, physical nervedamage, causalgia, reflex sympathetic dystrophy, sciatica, cervical,thoracic or lumbar radiculopathy, brachial plexopathy, lumbarplexopathy, neurodegenerative disorders, occipital neuralgia,intercostal neuralgia, supraorbital neuralgia, inguinal neuralgia,meralgia paresthetica, genitofemoral neuralgia, carpal tunnel syndrome,Morton's neuroma, post-mastectomy syndrome, post-thoracotomy syndrome,post-polio syndrome, Guillain-Barré syndrome, Raynaud's syndrome,coronary artery spasm (Printzmetal's or variant angina), visceralhyperalgesia (Pomonis, J. D. et al. J. Pharmacol. Exp. Ther. 2003, 306,387; Walker, K. M. et al., J. Pharmacol. Exp. Ther. 2003, 304(1),56-62), thalamic pain, cancer (e.g. pain caused by cancer, by treatmentof cancer by radiation or chemotherapy, or by nerve or bone lesionsassociated with cancer (see, Menendez, L. et al., Neurosci. Lett. 2005,393 (1), 70-73; Asai, H. et al., Pain 2005, 117, 19-29), or bonedestruction pain (see, Ghilardi, J. R. et al., J. Neurosci. 2005, 25,3126-31)), infection, or metabolic disease. Additionally, the compoundsmay be used to treat pain indications such as visceral pain, ocularpain, thermal pain, dental pain, capsaicin-induced pain (as well asother symptoms induced by capsaicin such as cough, lachrymation, andbronchospasm).

In another preferred embodiment, agents are administered to treat: itch,which may arise from various sources, such as dermatological orinflammatory disorders; or inflammatory disorders selected from thegroup consisting of: renal or hepatobiliary disorders, immunologicaldisorders, medication reactions and unknown/idiopathic conditions.Inflammatory disorders treatable with an inventive agent include, forexample, inflammatory bowel disease (IBD), Crohn's disease, andulcerative colitis (Geppetti, P. et al., Br. J. Pharmacol. 2004, 141,1313-20; Yiangou, Y. et al., Lancet 2001, 357, 1338-39; Kimball, E. S.et al., Neurogastroenterol. Motil., 2004, 16, 811), osteoarthritis(Szabo, A. et al., J. Pharmacol. Exp. Ther. 2005, 314, 111-119),psoriasis, psoriatic arthritis, rheumatoid arthritis, myasthenia gravis,multiple sclerosis, scleroderma, glomerulonephritis, pancreatitis,inflammatory hepatitis, asthma, chronic obstructive pulmonary disease,allergic rhinitis, uveitis, and cardiovascular manifestations ofinflammation including atherosclerosis, myocarditis, pericarditis, andvasculitis.

In another preferred embodiment, inner ear disorders are treated with aninventive agent. Such disorders include, for example, hyperacusis,tinnitus, vestibular hypersensitivity, and episodic vertigo.

In another preferred embodiment, tracheobronchial and diaphragmaticdysfunctions are treated with an inventive agent, including, forexample, asthma and allergy-related immune responses (Agopyan, N. etal., Am. J. Physiol. Lung Cell Mol. Physiol. 2004, 286, L563-72;Agopyan, N. et al., Toxicol. Appl. Pharmacol. 2003, 192, 21-35), cough(e.g., acute or chronic cough, or cough caused by irritation fromgastroesophageal reflux disease; see, Lalloo, U. G. et al., J. Appl.Physiol. 1995, 79(4), 1082-7), bronchospasm, chronic obstructivepulmonary disease, chronic bronchitis, emphysema, and hiccups(hiccoughs, singultus).

In yet another preferred embodiment, gastrointestinal and urinary tractdisorders are treated with an inventive agent, such as, bladderoveractivity, inflammatory hyperalgesia, visceral hyperreflexia of theurinary bladder, hemorrhagic cystitis (Dinis, P. et al., J. Neurosci.2004, 24, 11253-11263), interstitial cystitis (Sculptoreanu, A. et al.,Neurosci. Lett. 2005, 381, 42-46), inflammatory prostate disease,prostatitis (Sanchez, M. et al., Eur. J. Pharmacol. 2005, 515, 20-27),nausea, vomiting, intestinal cramping, intestinal bloating, bladderspasms, urinary urgency, defecation urgency and urge incontinence.

In another preferred embodiment, disorders associated with reduced bloodflow to the CNS or CNS hypoxia are treated with an inventive agent. Suchdisorders include, for example, head trauma, spinal injury,thromboembolic or hemorrhagic stroke, transient ischaemic attacks,cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus,perinatal asphyxia, Alzheimer's disease, and Huntington's Disease.

In other embodiments, agents are administered to treat other diseases,disorders, or conditions mediated through TRPV1 activity, such as:anxiety; learning or memory disorders; eye-related disorders (such asglaucoma, vision loss, increased intraocular pressure, andconjunctivitis); baldness (e.g., by stimulating hair growth); diabetes(including insulin-resistant diabetes or diabetic conditions mediated byinsulin sensitivity or secretion); obesity (e.g., through appetitesuppression); dyspepsia; biliary colic; renal colic; painful bladdersyndrome; inflamed esophagus; upper airway disease; urinaryincontinence; acute cystitis; and envenomations (such as marine, snake,or insect stings or bites, including jellyfish, spider, or stingrayenvenomations).

In especially preferred embodiments of the therapeutic methods of theinvention, effective amounts of the TRPV1 modulators of the presentinvention are administered to treat pain, itch, cough, asthma, orinflammatory bowel disease.

The term “treat” or “treating” as used herein is intended to refer toadministration of an agent or composition of the invention to a subjectfor the purpose of effecting a therapeutic or prophylactic benefitthrough modulation of TRPV1 activity. Treating includes reversing,ameliorating, alleviating, inhibiting the progress of, lessening theseverity of, or preventing a disease, disorder, or condition, or one ormore symptoms of such disease, disorder or condition mediated throughmodulation of TRPV1 activity. The term “subject” refers to a mammalianpatient in need of such treatment, such as a human. “Modulators” includeboth inhibitors and activators, where “inhibitors” refer to compoundsthat decrease, prevent, inactivate, desensitize or down-regulate TRPV1expression or activity, and “activators” are compounds that increase,activate, facilitate, sensitize, or up-regulate TRPV1 expression oractivity.

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the agents of thepresent invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the agent, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An exemplary dose is in therange of from about 0.001 to about 200 mg of agent per kg of subject'sbody weight per day, preferably about 0.05 to 100 mg/kg/day, or about 1to 35 mg/kg/day, or about 0.1 to 10 mg/kg daily in single or divideddosage units (e.g., BID, TID, QID). For a 70-kg human, an illustrativerange for a suitable dosage amount is from about 0.05 to about 7 g/day,or about 0.2 to about 2.5 g/day. Once improvement of the patient'sdisease, disorder, or condition has occurred, the dose may be adjustedfor preventative or maintenance treatment. For example, the dosage orthe frequency of administration, or both, may be reduced as a functionof the symptoms, to a level at which the desired therapeutic orprophylactic effect is maintained. Of course, if symptoms have beenalleviated to an appropriate level, treatment may cease. Patients may,however, require intermittent treatment on a long-term basis upon anyrecurrence of symptoms.

In addition, the agents of the invention may be used in combination withadditional active compounds in the treatment of the above conditions.The additional compounds may be coadministered separately with an agentof Formula (I) or included with such an agent as an additional activeingredient in a pharmaceutical composition according to the invention.In an exemplary embodiment, additional active compounds are those thatare known or discovered to be effective in the treatment of conditions,disorders, or diseases mediated by TRPV1 activity, such as another TRPV1modulator or a compound active against another target associated withthe particular condition, disorder, or disease. The combination mayserve to increase efficacy (e.g., by including in the combination acompound potentiating the potency or effectiveness of an agent accordingto the invention), decrease one or more side effects, or decrease therequired dose of the agent according to the invention. In oneillustrative embodiment, a composition according to the invention maycontain one or more additional active ingredients selected from opioids,NSAIDs (e.g., ibuprofen, cyclooxygenase-2 (COX-2) inhibitors, andnaproxen), gabapentin, pregabalin, tramadol, acetaminophen, and aspirin.

The agents of the invention are used, alone or in combination with oneor more other active ingredients, to formulate pharmaceuticalcompositions of the invention. A pharmaceutical composition of theinvention comprises: (a) an effective amount of a pharmaceutical agentin accordance with the invention; and (b) a pharmaceutically acceptableexcipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnot toxic, biologically intolerable, or otherwise biologicallyunsuitable for administration to a subject, such as an inert substance,added to a pharmacological composition or otherwise used as a vehicle,carrier, or diluent to facilitate administration of a pharmaceuticalagent and that is compatible therewith. Examples of excipients includecalcium carbonate, calcium phosphate, various sugars and types ofstarch, cellulose derivatives, gelatin, vegetable oils, and polyethyleneglycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the pharmaceutical agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the agents may beformulated to yield a dosage of, e.g., from about 0.05 to about 50 mg/kgdaily, or from about 0.05 to about 20 mg/kg daily, or from about 0.1 toabout 10 mg/kg daily.

Oral tablets may include the agent and any other active ingredientsmixed with compatible pharmaceutically acceptable excipients such asdiluents, disintegrating agents, binding agents, lubricating agents,sweetening agents, flavoring agents, coloring agents and preservativeagents. Suitable inert fillers include sodium and calcium carbonate,sodium and calcium phosphate, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol, and the like.Exemplary liquid oral excipients include ethanol, glycerol, water, andthe like. Starch, polyvinyl-pyrrolidone (PVP), sodium starch glycolate,microcrystalline cellulose, and alginic acid are exemplarydisintegrating agents. Binding agents may include starch and gelatin.The lubricating agent, if present, may be magnesium stearate, stearicacid or talc. If desired, the tablets may be coated with a material suchas glyceryl monostearate or glyceryl distearate to delay absorption inthe gastrointestinal tract, or may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, active ingredient may be mixed with asolid, semi-solid, or liquid diluent. Soft gelatin capsules may beprepared by mixing the active ingredient with water, an oil such aspeanut oil, sesame oil, or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, theagents of the invention may be provided in sterile aqueous solutions orsuspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms may be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses rangefrom about 1 to 1000 μg/kg/minute of agent admixed with a pharmaceuticalcarrier over a period ranging from several minutes to several days.

For topical administration, the agents may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the agents of theinvention may utilize a patch formulation to affect transdermaldelivery.

Agents may alternatively be administered in methods of this invention byinhalation, via the nasal or oral routes, e.g., in a spray formulationalso containing a suitable carrier.

Preferred agents useful in methods of the invention will now bedescribed by reference to illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I).

Referring to general Scheme A, compounds of Formula (I) may be preparedfrom β-ketoesters (VI), where X¹ is a suitable amino protecting group,such as a benzyl or carbamate group. Protected piperidones (V) arecommercially available or may be prepared according to known methods.Preferred protecting groups for amines include tert-butyl carbamate(Boc) or benzyl groups. β-Ketoesters (VI) may be prepared according togeneral techniques known in the art. For example, β-ketoesters (VI) maybe accessed from piperidones (V) by ring expansion of piperidones (V)with ethyl diazoacetate in the presence of a Lewis acid, such asBF₃.OEt, in a suitable solvent, such as Et₂O or CH₂Cl₂ or a mixturethereof, at temperatures ranging from about 0° C. to about roomtemperature (rt). β-Ketoesters (VI) may be reacted with amidines orcarboximidamides (VII), or with ureas or thioureas (VIII), for example,in the presence of NaOEt or KOtBu, in a solvent such as EtOH or tBuOH ora mixture thereof, at temperatures between rt and the reflux temperatureof the solvent, to form hydroxy pyrimidines (IX). Where the condensationis done with a urea or thiourea, in situ alkylation with an alkylchloride or bromide provides pyrimidines (IX) where R¹ is —S—C₁₋₆alkylor —O—C₁₋₆alkyl. The X¹ protecting group may be removed using knownmethods. For example, a Boc group may be removed with an acid such asTFA or HCl, in a solvent such as Et₂O, dioxane, EtOH, or MeOH or amixture thereof, to form amines (IX) where X¹=—H. Where an acid salt isobtained, the corresponding free base may be obtained by suitablegeneral methods known in the art. Preferably, the free base is obtainedby filtration of the salt through resin-bound carbonate using analcoholic solvent, preferably MeOH. Where X¹ is a benzyl group, thegroup may be removed according to standard methods, such ashydrogenation in the presence of a palladium catalyst such as Pd/C orPd(OH)₂/C, in a solvent such as EtOH. Hydroxy pyrimidines (IX) where X¹is —H may then be converted to amines (X) using known methods such asS_(N)-aryl substitution, or palladium-mediated cross-couplings.S_(N)-Aryl substitution may be accomplished by treatment of hydroxypyrimidines (XI), where X¹ is —H, with Ar-HAL (where HAL is halo), suchas 2-chloro-3-trifluoromethyl-pyridine, in the presence of a base suchK₂CO₃, in a polar solvent such as DMSO, at temperatures between about rtand the reflux temperature of the solvent. Palladium-mediatedcross-couplings are done by reacting Ar-HAL in the presence of apalladium catalyst. Preferably, hydroxy pyrimidines (IX), where X¹ is—H, are treated with Et₃N or (iPr)₂NEt, in suitable solvents, such asn-BuOH, tBuOH, t-amyl alcohol, DMF, DMSO, DME, or NMP, or a mixturethereof, at temperatures from about 100 to about 200° C. Pyrimidines (X)can then be activated for use in palladium-mediated cross-couplingreactions or S_(N)2 reactions by general procedures known in the art.For example, treatment with POCl₃, PCl₃, PBr₃, or POBr₃ affords thecorresponding halopyrimidines (XI) where Z is chloride or bromide.Treatment of pyrimidines (X) with trifluoromethane-sulfonic anhydride orN-phenyl-bis(trifluoromethanesulfonimide) in DCE, CH₂Cl₂, or THF, or amixture thereof, in the presence of a base such as pyridine, Et₃N,(iPr)₂NEt, or KOtBu, provides triflates (XI) where Z is —OSO₂CF₃. In apreferred embodiment, pyrimidines (X) are treated with POCl₃ in CH₃CN attemperatures from about 80 to about 100° C.

Substitution of pyrimidines (XI) with amines HN(R²)R³ to producecompounds of Formula (I) may be accomplished by various suitable methodswithin the routine purview of artisans. Where Z is Cl, substitution mayinvolve heating chloro-pyrimidines (XI) with suitable amines (XII) inalcoholic solvents such as MeOH, EtOH, tBuOH, n-BuOH, or t-amyl-OH, or amixture thereof, at temperatures from about rt to about the refluxtemperature of the solvent. Preferably, the solvent is n-BuOH and thetemperature is about 130° C. Alternatively, chloro-pyrimidines (XI) maybe reacted with amines (XII) in the presence of an acid catalyst,preferably p-toluenesulfonic acid or TFA, in toluene or dioxane, attemperatures from about 100 to about 150° C., to provide compounds ofFormula (I). Coupling of halides or triflates (XI) with amines (XII), inthe presence of a catalyst such as Pd(OAc)₂, Pd(PPh₃)₄, PdCl₂(PPh₃)₂, orPdCl₂(Po-tol₃)₂, in a solvent such as THF, 1,4-dioxane, DMA, DMF, DME,or toluene, or mixtures thereof, in the presence of a base such asNaOtBu, Na₂CO₃, K₂CO₃, Cs₂CO₃, or K₃PO₄, with or without an additivesuch as 2-(dicyclohexylphosphanyl)biphenyl (DCPB), also affordspyrimidines (I). In a preferred embodiment, coupling is accomplished inthe presence of Pd(OAc)₂ catalyst, DCPB, and NaOtBu in toluene attemperatures from about 100 to about 200° C. in a microwave reactor.

Referring to Scheme B, compounds of Formula (I) may be prepared by analternate general route. Protected piperidones (XV), such as1,4-dioxa-8-aza-spiro[4.5]decane (where PG is —O—(CH₂)₂—O—), may beconverted to aryl amines (XIV) by S_(N)-aryl substitution orpalladium-mediated cross-couplings as described in Scheme A.Deprotection of the protecting group using known general procedures,such as concentrated HCl, provides ketones (XV). Ketones (XV) may beprocessed into compounds of Formula (I) generally according to the ringexpansion, condensation, activation, and displacements described inScheme A.

Referring to Scheme C, thioethers (XVI), obtained as described in SchemeA, may be oxidized using generally known methods to provide sulfones(XVII). Displacement of the sulfone substituent is attained by reactionwith alcohols HO—C₁₋₆alkyl or amines HN(R^(a))R^(b) in solvents such asMeOH, EtOH, n-BuOH, THF, DMF, DMSO, or toluene, or a mixture thereof,with or without the presence of a suitable base such as NaOMe, NaOEt,KOtBu, NaH, Et₃N, (iPr)₂EtN, or pyridine, at temperatures between rt andthe reflux temperature of the solvent. Preferably, displacement withamines HN(R^(a))R^(b) is performed by heating with sulfones (XVII) intoluene in a sealed tube at 110° C.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, amines ofFormula (I) may be treated with trifluoroacetic acid, HCl, citric acid,H₂SO₄, methanesulfonic acid (MsOH), benzenesulfonic acid, orp-toluenesulfonic acid (TsOH) in a solvent such as Et₂O, EtOAc, CH₂Cl₂,THF, or MeOH, or a mixture thereof, to provide the corresponding saltforms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, or asracemic mixtures or mixtures of enantiomers, diastereomers, orregioisomers. Where regioisomeric or diastereomeric mixtures areobtained, isomers may be separated using conventional methods such aschromatography or crystallization. Where racemic (1:1) and non-racemic(not 1:1) mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one skilledin the art. Particularly useful separation methods may include chiralchromatography, recrystallization, diastereomeric salt formation, orderivatization into diastereomeric adducts followed by separation.

The following examples are provided to further illustrate aspects of theinvention and various preferred embodiments.

EXAMPLES

Chemistry:

In obtaining the characterization data described in the examples below,the following analytical protocols were followed unless otherwiseindicated.

NMR spectra were obtained on Bruker model DRX spectrometers. The formatof ¹H NMR data below is: chemical shift in ppm downfield of thetetramethylsilane reference (multiplicity, coupling constant J in Hz,integration).

Mass spectra were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in either positive or negative modes asindicated. Calculated mass corresponds to the exact mass.

Thin-layer chromatography was performed using Merck silica gel 60 F₂₅₄2.5 cm×7.5 cm 250 μm or 5.0 cm×10.0 cm 250 μm pre-coated silica gelplates. Preparative thin-layer chromatography was performed using EMScience silica gel 60 F₂₅₄ 20 cm×20 cm 0.5 mm pre-coated plates with a20 cm×4 cm concentrating zone.

Normal phase purification was typically done by normal phase flashcolumn chromatography (FCC) with RediSep® silica gel columns usingEtOAc/hexanes as eluent unless otherwise specified.

Reverse phase high performance liquid chromatography (HPLC) wasperformed under the following conditions: Instrument, Shimadzu; Column,Phenomenex Gemini column 5 μm C18 (150×21.2 mm) or Waters Xterra RP18OBD 5 μm (100×30 mm); Gradient, 95:5 to 0:100 water (0.05% TFA)/CH₃CN(0.05% TFA); Flow rate, 30 mL/min; Detection, UV at λ=254 nM.

Microwave reactions were carried out in either a CEM Discover® or aBiotage Initiator™ Microwave at specified temperatures.

Where solutions were “concentrated”, they were concentrated using arotary evaporator under reduced pressure. Unless otherwise specified,reaction solutions were stirred at room temperature (rt) under aN_(2(g)) atmosphere.

Hydrochloride salts were obtained by treating the corresponding freebases with HCl (4 N in dioxane) at rt. The mixtures were eitherconcentrated to obtain the HCl salt, or the resulting solid was isolatedby filtration.

Trifluoroacetic acid salts were obtained by purification of the crudereaction product by preparative reverse phase HPLC.

Intermediate A: 5-Oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester4-ethyl ester

To a 0° C. solution of 1-BOC-4-piperidone (20 g, 0.10 mol) in Et₂O (200mL) was added BF₃.Et₂O (14 mL, 0.11 mol) followed by drop-wise additionof ethyl diazoacetate (13.7 mL, 0.11 mol) over 1 h. After addition wascomplete, the mixture was stirred at 0° C. for 1 h. The mixture wasdiluted with 30% aq. Na₂CO₃ and water at 0° C. and extracted with EtOAc.The combined organic layers were dried (Na₂SO₄) and concentrated.Purification of the residue (FCC) afforded the title compound (25.6 g,98%). ¹H NMR (CDCl₃): 4.25-2.03 (m, 11H), 1.47-1.45 (d, J=7.8 Hz, 9H),1.31-1.24 (m, 3H).

Intermediate B:5-Oxo-1-(3-trifluoromethyl-pyridin-2-yl)-azepane-4-carboxylic acid ethylester

The title compound was prepared analogously to Intermediate A from3′-trifluoromethyl-2,3,5,6-tetrahydro-[1,2′]bipyridinyl-4-one (see U.S.Pat. Appl. Publ. US 2005/080095), using CH₂Cl₂ instead of Et₂O, and witha reaction time of 12 h at rt. MS (ESI): mass calcd. for C₁₅H₁₇F₃N₂O₃,330.12; m/z found, 331.1 [M+H]⁺. ¹H NMR (mixture of enol and keto forms;CDCl₃): 12.75 (s, 1.4H), 8.44-8.41 (m, 1.0H), 8.40-8.38 (m, 1.4H),7.90-7.83 (m, 2.5H), 7.04-6.99 (m, 1.0H), 6.97-6.92 (m, 1.5H), 4.26-4.19(m, 5.6H), 3.77-3.65 (m, 3.1H), 3.51-3.45 (m, 4.4H), 3.39-3.33 (m,4.2H), 3.02-2.94 (m, 1.0H), 2.83-2.75 (m, 4.1H), 2.70-2.66 (m, 3.1H),2.34-2.15 (m, 2.0H), 1.36-1.23 (m, 8.9H).

Example 1:(4-tert-Butyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

Step A. 4-Hydroxy-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylicacid tert-butyl ester

To solution of 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester4-ethyl ester (8.8 g, 30.8 mmol) in EtOH (308 mL) was added NaOEt (21%in EtOH; 38 mL) followed by formamidine acetate (4.8 g, 45.9 mmol). Themixture was heated at reflux for 2 h, then was concentrated, azeotropingwith toluene. The residue was dissolved in water and made basic viaaddition of 50% aq. NaOH. The aqueous layer was extracted with tolueneand then acidified to pH=7 with HOAc (precipitate formed). The mixturewas heated at 100° C. for 1 h, cooled to 0° C., and filtered to give thetitle compound (2.5 g, 31%), which was used without furtherpurification.

Step B. 6,7,8,9-Tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol

To a solution of4-hydroxy-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylic acidtert-butyl ester (1.0 g, 3.77 mmol) in CH₂Cl₂ (14 mL) was added 4 M HClin dioxane (4 mL, 15 mmol). After 24 h, the mixture was concentrated toafford the HCl salt (923 mg). The salt (200 mg, 1.0 mmol) was dissolvedin MeOH (10 mL) and filtered through quaternary amine resin, carbonateform (1.0 g) and concentrated to provide the title compound (159 mg,97%).

Step C.7-(3-Trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol

A solution of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (353 mg,1.76 mmol), 2-fluoro-3-trifluoromethyl-pyridine (582 mg, 3.53 mmol),iPr₂NEt (0.9 mL, 5.28 mmol), and t-amyl alcohol (5 mL) was heated in amicrowave at 180° C. for 5 h. The mixture was concentrated, diluted withwater, and extracted with EtOAc. The combined organic layers were dried(Na₂SO₄) and concentrated to give the title compound (185 mg, 34%),which was used in the next step without further purification.

Step D.4-Chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

To a solution of7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol(185 mg, 0.60 mmol) in CH₃CN (2 mL) was added POCl₃ (0.11 mL, 1.19mmol). The reaction mixture was heated at 90° C. for 2 h. The mixturewas cooled to rt, diluted with EtOAc, and quenched slowly with saturated(satd.) aq. NaHCO₃. The combined organic layers were dried (Na₂SO₄) andconcentrated. The crude residue was purified (FCC) to give the titlecompound (65 mg, 33%).

Step E

To a solution of4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine(27 mg, 0.085 mmol) in n-BuOH (1 mL) was added 4-tert-butylaniline (27μL, 0.17 mmol). After 2 h at 135° C., the mixture was cooled to rt,quenched with saturated aqueous (satd. aq.) NaHCO₃, and extracted withEtOAc. The combined organic layers were dried (Na₂SO₄) and concentrated.The residue was purified (FCC) to give the title compound (33 mg, 89%).MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅, 441.21; m/z found, 442.2 [M+H]⁺.¹H NMR (CDCl₃): 8.50 (s, 1H), 8.40-8.37 (m, 1H), 7.90-7.85 (m, 1H),7.46-7.36 (m, 4H), 6.98-6.93 (m, 1H), 6.45 (s, 1H), 3.70-3.65 (m, 2H),3.64-3.60 (m, 2H), 3.26-3.20 (m, 2H), 3.02-2.95 (m, 2H), 1.32 (s, 9H).Alternatively, the reaction of this step may be performed in themicrowave at 180° C. for 30 min.

Example 1A:(4-tert-Butyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-aminehydrochloride salt

The following Examples 2-16 were prepared using methods analogous tothose described in Example 1, substituting the appropriate amidines inStep A and amines in Step E.

Example 2:(4-Trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetra-hydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₁H₁₇F₆N₅, 453.14; m/z found, 454.1 [M+H]⁺.¹H NMR (CDCl₃): 8.56 (s, 1H), 8.39-8.36 (m, 1H), 7.89-7.86 (m, 1H), 7.68(d, J=8.8 Hz, 2H), 7.59 (d, J=8.8 Hz, 2H), 6.98-6.94 (m, 1H), 6.65 (s,1H), 3.68-3.64 (m, 2H), 3.63-3.59 (m, 2H), 3.27-3.22 (m, 2H), 3.04-3.00(m, 2H).

Example 2A:(4-Trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetra-hydro-5H-pyrimido[4,5-d]azepin-4-yl]-aminehydrochloride salt Example 3:(4-tert-Butyl-phenyl)-[2-cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₇H₃₀F₃N₅, 481.25; m/z found, 482.2 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.35 (m, 1H), 7.87-7.83 (m, 1H), 7.50-7.45 (m, 2H),7.36-7.31 (m, 2H), 6.94-6.91 (m, 1H), 6.40 (s, 1H), 3.66-3.53 (m, 4H),3.21-3.12 (m, 2H), 2.94-2.86 (m, 2H), 2.09-2.02 (m, 1H), 1.32 (s, 9H),1.11-1.06 (m, 2H), 0.97-0.92 (m, 2H).

Example 4:(4-Chloro-phenyl)-[2-cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₃H₂₁ClF₃N₅, 459.14; m/z found, 460.1 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.35 (m, 1H), 7.88-7.83 (m, 1H), 7.50-7.45 (m, 2H),7.30-7.26 (m, 2H), 6.97-6.91 (m, 1H), 6.41 (s, 1H), 3.65-3.55 (m, 4H),3.20-3.15 (m, 2H), 2.94-2.89 (m, 2H), 2.08-2.01 (m, 1H), 1.05-1.01 (m,2H), 0.97-0.92 (m, 2H).

Example 5:[2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₁F₆N₅, 493.17; m/z found, 494.1 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.35 (m, 1H), 7.88-7.85 (m, 1H), 7.73-7.65 (m, 2H),7.60-7.51 (m, 2H), 6.97-6.92 (m, 1H), 6.59 (s, 1H), 3.66-3.55 (m, 4H),3.23-3.15 (m, 2H), 2.99-2.90 (m, 2H), 2.12-2.05 (m, 1H), 1.09-0.95 (m,4H).

Example 5A:[2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminehydrochloride salt Example 6:(4-tert-Butyl-phenyl)-[2-phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₃₀H₃₀F₃N₅, 517.25; m/z found, 518.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.37 (m, 3H), 7.89-7.86 (m, 1H), 7.65-7.59 (m, 2H),7.49-7.39 (m, 5H), 6.97-6.91 (m, 1H), 6.54 (s, 1H), 3.73-3.69 (m, 2H),3.68-3.64 (m, 2H), 3.35-3.29 (m, 2H), 3.06-3.00 (m, 2H), 1.35 (s, 3H).

Example 7:[2-Phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₇H₂₁F₆N₅, 529.17; m/z found, 530.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.33 (m, 3H), 7.89-7.85 (m, 1H), 7.81 (d, J=8.5 Hz,2H), 7.65-7.63 (d, J=8.5 Hz, 2H), 7.49-7.43 (m, 3H), 6.98-6.93 (m, 1H),6.72 (s, 1H), 3.72-3.67 (m, 2H), 3.66-3.62 (m, 2H), 3.36-3.32 (m, 2H),3.11-3.02 (m, 2H).

Example 8:(4-tert-Butyl-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₇H₃₂F₃N₅, 483.26; m/z found, 484.2 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.35 (m, 1H), 7.87-7.83 (m, 1H), 7.50-7.45 (m, 2H),7.62-7.57 (m, 2H), 6.94-6.91 (m, 1H), 6.45 (s, 1H), 3.67-3.63 (m, 2H),3.62-3.58 (m, 2H), 3.21-3.17 (m, 2H), 3.05-2.97 (m, 1H), 2.95-2.90 (m,2H), 1.34-1.31 (m, 12H), 1.30 (s, 3H).

Example 9:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅, 495.19; m/z found, 496.1 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.36 (m, 1H), 7.88-7.84 (m, 1H), 7.79 (d, J=9.1 Hz,2H), 7.58 (d, J=8.8 Hz, 2H), 6.97-6.93 (m, 1H), 6.64 (s, 1H), 3.67-3.63(m, 2H), 3.61-3.57 (m, 2H), 3.24-3.20 (m, 2H), 3.09-3.00 (m, 1H),3.00-2.95 (m, 2H), 1.31 (d, J=6.86 Hz, 6H).

Example 9A:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminehydrochloride salt

¹H NMR (CD₃OD): 8.47-8.45 (m, 1H), 8.04 (dd, J=1.7, 7.8 Hz, 1H), 7.82(d, J=8.6 Hz, 2H), 7.75 (d, J=8.6 Hz, 2H), 7.18-7.14 (m, 1H), 3.71-3.67(m, 2H), 3.65-3.62 (m, 2H), 3.40-3.35 (m, 2H), 3.27-3.23 (m, 2H), 3.12(td, J=6.8, 13.6 Hz, 1H), 1.32 (d, J=6.8 Hz, 6H).

Example 10:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(3-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅, 495.19; m/z found, 496.1 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 8.30 (s, 1H), 7.91-7.88 (m, 1H),7.69-7.66 (m, 1H), 7.47-7.43 (m, 1H), 7.32-7.31 (m, 1H), 6.99-6.95 (m,1H), 6.63 (s, 1H), 3.70-3.66 (m, 2H), 3.64-3.61 (m, 2H), 3.26-3.22 (m,2H), 3.10-3.02 (m, 1H), 3.01-2.97 (m, 2H), 1.33 (d, J=6.9 Hz, 6H).

Example 11:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅O, 511.18; m/z found, 512.1 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.73-7.67 (m, 2H),7.20 (d, J=8.3 Hz, 2H), 6.97-6.93 (m, 1H), 6.53 (s, 1H), 3.67-3.64 (m,2H), 3.63-3.58 (m, 2H), 3.25-3.19 (m, 2H), 3.09-2.93 (m, 3H), 1.31 (d,J=6.8 Hz, 6H).

Example 12:[2-(4-Fluoro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₅H₂₇F₄N₅, 473.22; m/z found, 474.2 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.35 (m, 1H), 7.87-7.84 (m, 1H), 7.19-7.14 (m, 2H),7.03-6.96 (m, 2H), 6.95-6.90 (m, 1H), 4.65-4.59 (m, 1H), 3.77-3.70 (m,2H), 3.60-3.54 (m, 4H), 3.16-3.11 (m, 2H), 3.02-2.88 (m, 3H), 2.69-2.64(m, 2H), 1.30 (d, J=7.1 Hz, 6H).

Example 13:[2-(2-Chloro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₅H₂₇ClF₃N₅, 489.19; m/z found, 490.1 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.40-7.37 (m, 1H),7.25-7.16 (m, 3H), 6.96-6.92 (m, 1H), 4.73-4.67 (m, 1H), 3.84-3.78 (m,2H), 3.61-3.56 (m, 4H), 3.17-3.07 (m, 4H), 3.02-2.93 (m, 1H), 2.72-2.67(m, 2H), 1.31 (d, J=6.9 Hz, 6H).

Example 14:(3,4-Dichloro-benzyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₄H₂₄Cl₂F₃N₅, 509.14; m/z found, 510.1[M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.36 (m, 1H), 7.89-7.86 (m, 1H), 7.50 (d,J=2.2 Hz, 1H), 7.40 (d, J=8.2 Hz, 1H), 7.22-7.19 (m, 1H), 6.96-6.93 (m,1H), 4.99-4.94 (m, 1H), 4.68 (d, J=6.0 Hz, 2H), 3.64-3.57 (m, 4H),3.18-3.14 (m, 2H), 2.99-2.91 (m, 1H), 2.82-2.79 (m, 2H), 1.26 (d, J=6.9Hz, 6H).

Example 15:(4-tert-Butyl-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₅H₂₈F₃N₅, 455.23; m/z found, 456.9 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.89-7.86 (m, 1H), 7.53-7.50 (m, 2H),7.39-7.35 (m, 2H), 6.97-6.93 (m, 1H), 6.50 (s, 1H), 3.66-3.59 (m, 4H),3.22-3.18 (m, 2H), 2.96-2.93 (m, 2H), 2.55 (s, 3H), 1.34 (s, 9H).

Example 16:[2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₂H₁₉F₆N₅, 467.15; m/z found, 468.1 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.90-7.87 (m, 1H), 7.74 (d, J=8.5 Hz,2H), 7.60 (d, J=8.8 Hz, 2H), 7.00-6.95 (m, 1H), 6.66 (s, 1H), 3.67-3.64(m, 2H), 3.63-3.59 (m, 2H), 3.25-3.20 (m, 2H), 3.02-2.98 (m, 2H), 2.59(s, 3H).

Example 17:(5-Trifluoromethyl-pyridin-2-yl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

The title compound was synthesized in a manner similar to Example 1 withmodifications to Step E as follows:

Step E

To a solution of4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine(38 mg, 0.12 mmol), 4-trifluoromethyl-amino-pyridine (28 mg, 0.17 mmol),and NaOtBu (16 mg, 0.16 mmol) in toluene (1.2 mL) in a microwave vialwas added a solution of Pd(OAc)₂ (0.4 mg, 0.002 mmol) and2-(dicyclohexylphosphino)biphenyl (DCPB) (1.2 mg, 0.004 mmol) in toluene(1 mL). The mixture was flushed with N_(2(g)) and heated in a microwaveat 200° C. for 30 min. The mixture was cooled, filtered through a plugof diatomaceous earth, and concentrated. The residue was purified (FCC)to afford the title compound (35 mg, 66%). MS (ESI): mass calcd. forC₂₀H₁₆F₆N₆, 454.13; m/z found, 453.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.65 (s,1H), 8.61 (d, J=8.8 Hz, 1H), 8.54-8.51 (m, 1H), 8.41-8.38 (m, 1H),7.95-7.85 (m, 2H), 7.64 (s, 1H), 7.01-6.95 (m, 1H), 3.67-3.57 (m, 4H),3.31-3.25 (m, 2H), 3.14-3.07 (m, 2H).

The following Examples 18-25 below were prepared using methods analogousto those described in Example 17, substituting the appropriate amidinesin Step A and amines in Step E.

Example 18:Isoquinolin-1-yl-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₃H₁₉F₃N₆, 436.16; m/z found, 437.1 [M+H]⁺.¹H NMR (CDCl₃): 8.83 (d, J=8.0 Hz, 1H), 8.65 (s, 1H), 8.42-8.39 (m, 1H),7.90-7.86 (m, 1H), 7.69-7.64 (m, 1H), 7.60-7.53 (m, 2H), 7.32-7.29 (m,1H), 6.97-6.93 (m, 1H), 6.71 (d, J=6.9 Hz, 1H), 3.64-3.54 (m, 6H),3.30-3.24 (m, 2H).

Example 19:[2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₀F₆N₆, 494.17; m/z found, 495.1 [M+H]⁺.¹H NMR (CDCl₃): 8.54-8.47 (m, 2H), 8.40-8.37 (m, 1H), 7.93-7.84 (m, 2H),7.54 (s, 1H), 7.00-6.89 (m, 1H), 3.62-3.54 (m, 4H), 3.24-3.19 (m, 2H),3.04-2.99 (m, 2H), 2.19-2.08 (m, 1H), 1.13-1.08 (m, 2H), 1.05-1.00 (m,2H).

Example 20:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₂F₆N₆, 496.18; m/z found, 497.1 [M+H]⁺.¹H NMR (CDCl₃): 8.73 (d, J=9.1 Hz, 1H), 8.50 (s, 1H), 8.40-8.37 (m, 1H),7.94-7.90 (m, 1H), 7.88-7.85 (m, 1H), 7.60 (s, 1H), 6.98-6.93 (m, 1H),3.65-3.54 (m, 4H), 3.28-3.20 (m, 2H), 3.14-3.01 (m, 3H), 1.34 (d, J=6.9Hz, 6H).

Example 20A:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-aminehydrochloride salt Example 21:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-quinolin-3-yl-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₃N₆, 478.21; m/z found, 479.1 [M+H]⁺.¹H NMR (CDCl₃): 8.99 (d, J=2.2 Hz, 1H), 8.86 (d, J=2.5 Hz, 1H),8.43-8.40 (m, 1H), 8.07 (d, J=8.2 Hz, 1H), 7.92-7.88 (m, 1H), 7.83-7.80(m, 1H), 7.65-7.61 (m, 1H), 7.58-7.54 (m, 1H), 7.00-6.95 (m, 1H), 6.75(s, 1H), 3.74-3.70 (m, 2H), 3.67-3.63 (m, 2H), 3.29-3.25 (m, 2H),3.14-3.05 (m, 3H), 1.38 (d, J=6.9 Hz, 6H).

Example 22:[2-Phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

MS (ESI): mass calcd. for C₂₆H₂₀F₆N₆, 530.17; m/z found, 531.1 [M+H]⁺.¹H NMR (CDCl₃): 8.76 (d, J=8.8 Hz, 1H), 8.57 (s, 1H), 8.44-8.39 (m, 3H),8.04-8.00 (m, 1H), 7.91-7.88 (m, 1H), 7.67 (s, 1H), 7.55-7.48 (m, 3H),7.00-6.96 (m, 1H), 3.72-3.62 (m, 4H), 3.41-3.36 (m, 2H), 3.18-3.11 (m,2H).

Example 23:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine

MS (ESI): mass calcd. for C₂₃H₂₂F₆N₆, 496.18; m/z found, 497.1 [M+H]⁺.¹H NMR (CDCl₃): 8.86 (d, J=2.5 Hz, 1H), 8.54-8.51 (m, 1H), 8.42-8.39 (m,1H), 7.91-7.90 (m, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.01-6.96 (m, 1H), 6.71(s, 1H), 3.70-3.67 (m, 2H), 3.64-3.60 (m, 2H), 3.29-3.24 (m, 2H),3.12-3.02 (m, 3H), 1.33 (d, J=6.6 Hz, 6H).

Example 24:2-Methyl-7-(3-(trifluoromethyl)pyridin-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₁H₁₈F₆N₆, 468.15; m/z found, 469.8 [M+H]⁺.¹H NMR (CDCl₃): 8.84 (d, J=2.5 Hz, 1H), 8.47-8.43 (m, 1H), 8.40-8.38 (m,1H), 7.90-7.87 (m, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.00-6.96 (m, 1H), 6.81(s, 1H), 3.67-3.63 (m, 2H), 3.62-3.59 (m, 2H), 3.25-3.22 (m, 2H),3.06-3.03 (m, 2H), 2.58 (s, 3H).

Example 25:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-phenoxy-phenyl)-amine

MS (ESI): mass calcd. for C₂₉H₂₈F₃N₅O, 519.22; m/z found, 520.2 [M+H]⁺.¹H NMR (CDCl₃): 8.42-8.39 (m, 1H), 7.90-7.87 (m, 1H), 7.67-7.62 (m, 2H),7.37-7.32 (m, 2H), 7.12-7.08 (m, 1H), 7.05-7.01 (m, 4H), 6.98-6.94 (m,1H), 6.48 (s, 1H), 3.70-3.66 (m, 2H), 3.65-3.61 (m, 2H), 3.24-3.21 (m,2H), 3.07-2.94 (m, 3H), 1.32 (d, J=6.9 Hz, 6H).

Example 26:(4-Trifluoromethyl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

The title compound was synthesized a manner similar to Example 1 withmodifications to Step C as follows and using 4-trifluoromethylaniline inStep E:

Step C.7-(4-Trifluoromethyl-pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol

A solution of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (60 mg,0.30 mmol), 2-chloro-4-tritrifluoropyrimidine (36 μL, 0.30 mmol), andEt₃N (0.11 mL, 0.81 mmol) in DMF (1.2 mL) was heated at 120° C. for 2 h.The mixture was cooled to rt, diluted with water, and extracted withEtOAc. The combined organic layers were dried (Na₂SO₄) and concentratedto give the title compound (69 mg, 68%), which was used without furtherpurification.

Step E

MS (ESI): mass calcd. for C₂₀H₁₆F₆N₆, 454.13; m/z found, 455.1 [M+H]⁺.¹H NMR (CDCl₃): 8.56 (s, 1H), 8.53 (d, J=5.2 Hz, 1H), 7.67 (d, J=8.2 Hz,2H), 7.59 (d, J=8.5 Hz, 2H), 6.80 (d, J=5.2 Hz, 1H), 6.60 (s, 1H),4.30-4.26 (m, 2H), 4.13-4.09 (m, 2H), 3.31-3.26 (m, 2H), 2.96-2.90 (m,2H).

Example 27:(7-Pyrimidin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine

The title compound was prepared analogously to the methodology describedin Example 26, substituting 2-chloropyrimidine in Step C. MS (ESI): masscalcd. for C₁₉H₁₇F₃N₆, 386.15; m/z found, 387.1 [M+H]⁺. ¹H NMR (CDCl₃):8.57 (s, 1H), 8.35 (d, J=4.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H), 7.59 (d,J=8.8 Hz, 2H), 6.61 (s, 1H), 6.55-6.52 (m, 1H), 4.28-4.23 (m, 2H),4.11-4.06 (m, 2H), 3.32-3.25 (m, 2H), 2.95-2.90 (m, 2H).

Example 28:(7-Pyrazin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine

The title compound was prepared analogously to Example 26, substituting2-chloropyrazine in Step C. MS (ESI): mass calcd. for C₁₉H₁₇F₃N₆,386.15; m/z found, 387.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.56 (s, 1H), 8.12-8.10(m, 1H), 8.08-8.06 (m, 1H), 7.86 (d, J=2.7 Hz, 1H), 7.67 (d, J=8.8 Hz,2H), 7.59 (d, J=8.8 Hz, 2H), 6.57 (s, 1H), 4.25-4.20 (m, 2H), 3.92-3.88(m, 2H), 3.38-3.34 (m, 2H), 2.96-2.91 (m, 2H).

Example 29:(7-Quinoxalin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine

The title compound was prepared analogously to Example 26, substituting2-chloroquinoxaline in Step C. MS (ESI): mass calcd. for C₂₃H₁₉F₃N₆,436.16; m/z found, 437.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.58 (d, J=11.2 Hz,2H), 7.92-7.89 (m, 1H), 7.73-7.66 (m, 3H), 7.63-7.58 (m, 3H), 7.44-7.39(m, 1H), 6.61 (s, 1H), 4.42-4.35 (m, 2H), 4.16-4.07 (m, 2H), 3.46-3.38(m, 2H), 3.09-3.02 (m, 2H).

Example 30:[7-(3-Chloro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

The title compound was prepared analogously to Example 26, substituting2,3-dichloropyridine in Step C. MS (ESI): mass calcd. for C₂₀H₁₇ClF₃N₅,419.11; m/z found, 420.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.57 (s, 1H), 8.15-8.13(m, 1H), 7.68 (d, J=9.3 Hz, 2H), 7.63-7.58 (m, 3H), 6.84-6.79 (m, 1H),6.65 (s, 1H), 3.77-3.67 (m, 4H), 3.31-3.24 (m, 2H), 3.08-3.01 (m, 2H).

Example 31:(4-tert-Butyl-phenyl)-[7-(6-chloro-5-methyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

The title compound was prepared analogously to Example 26, substituting4,6-dichloro-5-methylpyrimidine in Step C and 4-tert-butyl-aniline inStep E. MS (ESI−): mass calcd. for C₂₃H₂₇ClN₆, 422.20; m/z found, 421.2[M−H]⁻. ¹H NMR (CDCl₃): 8.50 (s, 1H), 8.33 (s, 1H), 7.44-7.36 (m, 4H),6.43 (s, 1H), 3.91-3.84 (m, 2H), 3.81-3.75 (m, 2H), 3.26-3.19 (m, 2H),3.04-2.98 (m, 2H), 2.31 (s, 3H), 1.32 (s, 9H).

Example 32:(4-tert-Butyl-phenyl)-[7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

The title compound was prepared analogously to Example 26, substituting2-chloro-3-methylquinoline in Step C and 4-tert-butyl-aniline in Step E.MS (ESI−): mass calcd. for C₂₇H₃₀N₆, 438.25; m/z found, 437.2 [M−H]⁻. ¹HNMR (CDCl₃): 8.51 (s, 1H), 7.90-7.87 (m, 1H), 7.79-7.76 (m, 1H),7.60-7.55 (m, 1H), 7.53-7.48 (m, 1H), 7.43-7.36 (m, 4H), 6.47 (s, 1H),3.80-3.76 (m, 2H), 3.74-3.70 (m, 2H), 3.31-3.26 (m, 2H), 3.07-3.02 (m,2H), 2.75 (s, 3H), 1.32 (s, 9H).

Example 33:(4-tert-Butyl-phenyl)-[2-isopropyl-7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

The title compound was prepared analogously to Example 26, substituting2-chloro-3-methylquinoline in Step C and 4-tert-butyl-aniline in Step E.MS (ESI−): mass calcd. for C₃₀H₃₆N₆, 480.3; m/z found, 479.3 [M−H]⁻. ¹HNMR (CDCl₃): 7.89-7.86 (m, 1H), 7.78-7.76 (m, 1H), 7.62-7.54 (m, 3H),7.51-7.47 (m, 1H), 7.37-7.34 (m, 2H), 6.48 (s, 1H), 3.77-3.73 (m, 2H),3.71-3.67 (m, 2H), 3.29-3.23 (m, 2H), 3.02-2.97 (m, 3H), 2.74 (s, 3H),1.33-1.32 (m, 12H), 1.31 (s, 3H).

Example 34:[2-Isopropyl-7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

The title compound was prepared analogously to Example 26, substituting2-chloro-3-methylquinoline in Step C. MS (ESI): mass calcd. forC₂₇H₂₇F₃N₆, 492.22; m/z found, 493.2 [M+H]⁺. ¹H NMR (CDCl₃): 7.89-7.86(m, 1H), 7.81-7.75 (m, 3H), 7.61-7.55 (m, 3H), 7.53-7.48 (m, 1H), 6.67(s, 1H), 3.78-3.75 (m, 2H), 3.72-3.68 (m, 2H), 3.32-3.27 (m, 2H),3.09-3.02 (m, 3H), 2.75 (s, 3H), 1.32 (d, J=7.1 Hz, 6H).

Example 35:[2-Isopropyl-7-(3-trifluoromethyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

The title compound was prepared analogously to Example 26, substituting2-chloro-3-trifluoromethylquinoline in Step C. MS (ESI): mass calcd. forC₂₇H₂₄F₆N₆, 546.2; m/z found, 547.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.06-8.03(m, 1H), 7.88-7.71 (m, 4H), 7.65-7.57 (m, 3H), 6.66 (s, 1H), 3.87-3.77(m, 4H), 3.33-3.27 (m, 2H), 3.10-3.00 (m, 3H), 1.32 (d, J=6.8 Hz, 6H).

Example 36:[2-Isopropyl-7-(3-methanesulfonyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

The title compound was prepared analogously to Example 26, substituting2-chloro-3-(methylsulfonyl)pyridine (see, Ponticello, G. S. et al., J.Org. Chem. 1979, 44(17), 3080-3082) in Step C. MS (ESI): mass calcd. forC₂₄H₂₆F₃N₅O₂S, 505.18; m/z found, 506.1 [M+H]⁺. ¹H NMR (CDCl₃):8.54-8.51 (m, 1H), 8.38-8.34 (m, 1H), 7.80 (d, J=8.3 Hz, 2H), 7.60 (d,J=8.6 Hz, 2H), 7.25-7.21 (m, 1H), 6.89 (s, 1H), 3.60-3.55 (m, 2H),3.54-3.50 (m, 2H), 3.24-3.20 (m, 2H), 3.11-2.99 (m, 6H), 1.32 (d, J=6.8Hz, 6H).

Example 37:(4-tert-Butyl-phenyl)-(7-phthalazin-1-yl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl)-amine

The title compound was synthesized in a manner similar to Example 1 withmodifications to Step C as follows and using 4-tert-butyl-aniline inStep E:

Step C.7-Phthalazin-1-yl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-ol

A solution of 6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (50 mg,0.33 mmol), 1,4-dichlorophthalazine (55 mg, 0.28 mmol), and Et₃N (0.11mL, 0.81 mmol) in DMF (5 mL) was heated at 120° C. for 2 h. The mixturewas cooled to rt, diluted with water, and extracted with EtOAc. Thecombined organic layers were dried (Na₂SO₄) and concentrated to give7-(4-chloro-phthalazin-1-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol(50 mg, 55%), of which 23 mg (0.14 mmol) was treated with ammoniumformate (116 mg, 1.85 mmol) and Pd(OH)₂/C (14 mg, 0.08 mmol) inMeOH/dioxane (1:1; 4 mL). After 1 h at 100° C., the mixture was cooledrt, filtered through diatomaceous earth, and concentrated to give thetitle compound, which was carried on to Step D as in Example 1. MS(ESI−): mass calcd. for C₂₆H₂₈N₆, 424.24; m/z found, 423.2 [M−H]⁻. ¹HNMR (CDCl₃): 9.13 (s, 1H), 8.51 (s, 1H), 8.08-8.04 (m, 1H), 7.91-7.80(m, 3H), 7.48-7.36 (m, 4H), 6.56 (s, 1H), 4.04-3.97 (m, 2H), 3.96-3.89(m, 2H), 3.37-3.30 (m, 2H), 3.20-3.08 (m, 2H), 1.32 (s, 9H).

Example 38:(4-tert-Butyl-phenyl)-[7-(5-methyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

The title compound was prepared analogously to Example 37 using4,6-dichloro-5-methyl pyrimidine in Step C. MS (ESI): mass calcd. forC₂₃H₂₈N₆, 388.24; m/z found, 389.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.53 (s, 1H),8.49 (s, 1H), 8.09 (s, 1H), 7.43-7.35 (m, 4H), 6.43 (s, 1H), 3.97-3.94(m, 2H), 3.88-3.84 (m, 2H), 3.25-3.21 (m, 2H), 3.03-2.97 (m, 2H), 2.28(s, 3H), 1.31 (s, 9H).

Example 39:[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

Step A.2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol

To solution of KOtBu (1.3 g, 5.77 mmol) in tBuOH (32 mL) was added5-oxo-1-(3-trifluoromethyl-pyridin-2-yl)-azepane-4-carboxylic acid ethylester (Intermediate B; 1.27 g, 3.85 mmol), followed bypiperidine-1-carboximidamide hydrobromide (1.2 g, 5.77 mmol). Afterheating at reflux for 24 h, the mixture was cooled and concentrated. Theresidue was dissolved in water and CH₂Cl₂. The aqueous layer wasacidified to pH=7 with HOAc. The layers were separated and the aqueouslayer was extracted with CH₂Cl₂. The combined organic layers were dried(Na₂SO₄) and concentrated. The residue was triturated with Et₂O andfiltered. The filtrate was concentrated and the residue was purified(FCC) to give the title compound (776.4 g, 51%—combined filtered andchromatographed).

Step B.4-Chloro-2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

To a solution of2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol(435 mg, 1.11 mmol) in CH₃CN (9 mL) was added POCl₃ (0.41 mL, 4.43mmol). After 1.5 h at 80° C., the mixture was cooled to rt, diluted withEtOAc, and quenched slowly with satd. aq. NaHCO₃. The organic layerswere combined, dried (Na₂SO₄), and concentrated. The crude residue waspurified (FCC) to give the title compound (160 mg, 35%).

Step C.[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

To a solution of4-chloro-2-piperidin-1-yl-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine(50 mg, 0.12 mmol), 4-trifluoromethyl aniline (0.02 mL, 0.18 mmol), andNaOtBu (16 mg, 0.17 mmol) in toluene (1.5 mL) in a microwave vial wasadded a solution of Pd(OAc)₂ (0.4 mg, 0.002 mmol) and DCPB (1.3 mg,0.004 mmol) in toluene (1 mL). The mixture was flushed with N_(2(g)) andheated in a microwave at 200° C. for 50 min. The mixture was cooled andfiltered through a plug of diatomaceous earth. The filtrate wasconcentrated and the residue was purified (FCC) to afford the titlecompound (48 mg, 89%). MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆, 536.21; m/zfound, 537.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.87 (d, J=1.8Hz, 1H), 7.65 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.8 Hz, 2H), 6.97-6.91 (m,1H), 6.49 (s, 1H), 3.77-3.71 (m, 4H), 3.62-3.54 (m, 4H), 3.10-3.06 (m,2H), 2.89-2.84 (m, 2H), 1.70-1.56 (m, 6H).

Example 39A:[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminehydrochloride salt

¹H NMR (CD₃OD): 8.47-8.45 (m, 1H), 8.05 (dd, J=7.8, 1.8 Hz, 1H), 7.74(q, J=8.8 Hz, 4H), 7.16 (dd, J=7.8, 4.8 Hz, 1H), 3.74-3.69 (m, 4H),3.64-3.59 (m, 2H), 3.57-3.54 (m, 2H), 3.31-3.27 (m, 2H), 3.13-3.02 (m,2H), 1.80-1.72 (m, 2H), 1.72-1.65 (m, 4H).

Example 39B:[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminesulfate salt

¹H NMR (CD₃OD): 8.48-8.45 (m, 1H), 8.05 (dd, J=7.8, 1.6 Hz, 1H),7.78-7.68 (m, 4H), 7.19-7.13 (m, 1H), 3.75-3.69 (m, 4H), 3.65-3.59 (m,2H), 3.58-3.53 (m, 2H), 3.33-3.28 (m, 2H), 3.13-3.09 (m, 2H), 1.79-1.62(m, 6H).

The following Examples 40-45 were prepared using methodology similar tothat described in Example 39, substituting the appropriatecarboximidamides in Step A.

Example 40:[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₅H₂₄F₆N₆O, 538.19; m/z found, 539.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.89-7.85 (m, 1H), 7.63 (d, J=9.1 Hz,2H), 7.57 (d, J=9.1 Hz, 2H), 6.98-6.92 (m, 1H), 6.53 (s, 1H), 3.80-3.71(m, 8H), 3.63-3.54 (m, 4H), 3.13-3.06 (m, 2H), 2.92-2.86 (m, 2H).

Example 40A:[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminehydrochloride salt

¹H NMR (CD₃OD): 8.49-8.46 (m, 1H), 8.05 (dd, J=1.7, 7.4 Hz, 1H), 7.75(s, 4H), 7.17 (dd, J=4.9, 7.4 Hz, 1H), 3.79-3.75 (m, 4H), 3.73-3.71 (m,4H), 3.65-3.62 (m, 2H), 3.59-3.55 (m, 2H), 3.31-3.29 (m, 2H), 3.15-3.11(m, 2H).

Example 41:[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₇O, 539.19; m/z found, 540.2 [M+H]⁺.¹H NMR (CDCl₃): 8.52-8.51 (m, 1H), 8.42-8.40 (m, 1H), 8.38 (d, J=8.8 Hz,1H), 7.92-7.87 (m, 2H), 7.49-7.46 (m, 1H), 6.99-6.95 (m, 1H), 3.84-3.77(m, 8H), 3.60-3.54 (m, 4H), 3.15-3.10 (m, 2H), 2.97-2.94 (m, 2H).

Example 42:(4-tert-Butyl-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₉H₃₅F₃N₆, 524.29; m/z found, 525.3 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.36 (m, 1H), 7.87-7.84 (m, 1H), 7.50-7.46 (m, 2H),7.35-7.31 (m, 2H), 6.94-6.89 (m, 1H), 6.31 (s, 1H), 3.76-3.71 (m, 4H),3.63-3.55 (m, 4H), 3.09-3.03 (m, 2H), 2.86-2.81 (m, 2H), 1.67-1.57 (m,6H), 1.32 (s, 9H).

Example 43:N²,N²-Dimethyl-N⁴-(6-trifluoromethyl-pyridin-3-yl)-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

Example 43B:N²,N²-Dimethyl-N⁴-(6-trifluoromethyl-pyridin-3-yl)-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₂H₂₁F₆N₇, 497.18; m/z found, 498.8 [M+H]⁺.¹H NMR (CDCl₃): 9.04 (d, J=1.9 Hz, 1H), 8.76 (s, 1H), 8.39 (d, J=4.4 Hz,1H), 8.16-8.13 (m, 1H), 8.03-8.00 (m, 1H), 7.74 (d, J=8.2 Hz, 1H),7.12-7.08 (m, 1H), 3.67-3.62 (m, 4H), 3.38-3.33 (m, 2H), 3.22 (s, 6H),3.12-3.08 (m, 2H).

Example 44:N²,N²-Dimethyl-N⁴-(5-trifluoromethyl-pyridin-2-yl)-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₂H₂₁F₆N₇, 497.18; m/z found, 498.8 [M+H]⁺.¹H NMR (CDCl₃): 8.58 (d, J=9.1 Hz, 1H), 8.51-8.49 (m, 1H), 8.42-8.40 (m,1H), 7.90-7.86 (m, 2H), 7.48 (s, 1H), 6.98-6.94 (m, 1H), 3.59-3.54 (m,4H), 3.21 (s, 6H), 3.14-3.10 (m, 2H), 2.95-2.92 (m, 2H).

Example 45:N⁴-(3-Chloro-4-trifluoromethyl-phenyl)-N²,N²-dimethyl-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

The title compound was synthesized like Example 39 with modifications toStep C as follows:

Step C

A mixture of[4-chloro-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-2-yl]-dimethyl-amine(50 mg, 0.14 mmol), 3-chloro-4-trifluoro-methylaniline (40 mg, 0.20mmol), and p-toluenesulfonic acid (51 mg, 0.27 mmol) in toluene (2 mL)was heated in a sealed tube at 120° C. for 18 h. The mixture was cooled,diluted with satd. aq. NaHCO₃, and extracted with CH₂Cl₂. The organiclayer was dried (MgSO₄) and concentrated. The residue was purified (FCC)to give the title compound (55 mg, 78%). MS (ESI): mass calcd. forC₂₃H₂₁ClF₆N₆, 530.14; m/z found, 531.8 [M+H]⁺. ¹H NMR (CD₃OD): 8.43-8.40(m, 1H), 8.25 (d, J=1.9 Hz, 1H), 8.08-7.98 (m, 1H), 7.66-7.62 (m, 1H),7.57 (d, J=8.8 Hz, 1H), 7.11-7.08 (m, 1H), 3.45-3.39 (m, 4H), 3.33-3.31(m, 1H), 3.13 (s, 6H), 3.06-3.03 (m, 2H), 2.97-2.93 (m, 2H).

Example 46:(4-Bromo-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

The title compound was prepared using methods similar to those inExample 1 with modifications to Step E as follows:

Step E

A mixture of4-chloro-2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine(50 mg, 0.14 mmol), 4-bromoaniline (35 mg, 0.36 mmol), andp-toluenesulfonic acid (51 mg, 0.27 mmol) in toluene (2 mL) was heatedin a sealed tube at 130° C. for 18 h. The mixture was cooled, dilutedwith satd. aq. NaHCO₃, and extracted with EtOAc. The organic layer wasdried (Na₂SO₄) and concentrated. The residue was purified (FCC) to givethe title compound (57 mg, 77%). MS (ESI): mass calcd. for C₂₃H₂₃BrF₃N₅,505.11; m/z found, 506.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.39 (m, 1H),7.90-7.87 (m, 1H), 7.61-7.56 (m, 2H), 7.48-7.43 (m, 2H), 6.99-6.95 (m,1H), 6.49 (s, 1H), 3.68-3.65 (m, 2H), 3.63-3.60 (m, 2H), 3.25-3.21 (m,2H), 3.08-2.99 (m, 1H), 2.98-2.94 (m, 2H), 1.32 (d, J=6.9 Hz, 6H).

Example 47:(4-tert-Butyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

The title compound was synthesized in accordance with Example 39 withmodifications to Step C as follows:

Step C

To a solution of4-chloro-2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine(30 mg, 0.08 mmol) in n-BuOH (2 mL) was added 4-tert-butylaniline (23μL, 0.15 mmol). The mixture was heated in the microwave at 180° C. for90 min, then was cooled to rt, diluted with MeOH, and filtered throughquaternary amine resin, carbonate form (500 mg). The filtrate wasconcentrated and the residue was purified (FCC) to give the titlecompound (39 mg, 99%). MS (ESI): mass calcd. for C₂₈H₃₃F₃N₆O, 526.27;m/z found, 527.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.87 (d,J=1.8 Hz, 1H), 7.48-7.43 (m, 2H), 7.37-7.31 (m, 2H), 6.96-6.89 (m, 1H),6.35 (s, 1H), 3.80-3.70 (m, 8H), 3.64-3.54 (m, 4H), 3.11-3.04 (m, 2H),2.88-2.82 (m, 2H), 1.33 (s, 9H).

The following Examples 48-51 were prepared analogously to the methodsused in Example 47, substituting the appropriate carboximidamides inStep A and amines in Step C.

Example 48:N⁴-(4-tert-Butyl-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₆H₃₁F₃N₆, 484.26; m/z found, 485.9 [M+H]⁺.

Example 48:N⁴-(4-tert-Butyl-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.47-8.45 (m, 1H), 8.05-8.02 (m, 1H), 7.51-7.47 (m, 2H),7.46-7.42 (m, 2H), 7.17-7.13 (m, 1H), 3.64-3.60 (m, 2H), 3.57-3.53 (m,2H), 3.30-3.27 (m, 2H), 3.18 (s, 6H), 3.11-3.06 (m, 2H), 1.35 (s, 9H).

Example 49:N²,N²-Dimethyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₃H₂₂F₆N₆, 496.18; m/z found, 497.8 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.89-7.86 (m, 1H), 7.73 (d, J=8.8 Hz,2H), 7.57 (d, J=8.8 Hz, 2H), 6.97-6.93 (m, 1H), 6.55 (s, 1H), 3.62-3.56(m, 4H), 3.18 (s, 6H), 3.13-3.09 (m, 2H), 2.90-2.87 (m, 2H).

Example 50:N⁴-(4-Chloro-phenyl)-N₂,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

Example 50B:N⁴-(4-Chloro-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₂H₂₂ClF₃N₆, 462.15; m/z found, 463.8 [M+H]⁺.¹H NMR (CD₃OD): 8.47-8.45 (m, 1H), 8.05-8.02 (m, 1H), 7.57-7.53 (m, 2H),7.42-7.38 (m, 2H), 7.17-7.13 (m, 1H), 3.63-3.59 (m, 2H), 3.57-3.53 (m,2H), 3.31-3.27 (m, 2H), 3.18 (s, 6H), 3.10-3.06 (m, 2H).

Example 51:N⁴-(4-Trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₁H₁₈F₆N₆, 468.15; m/z found, 469.1 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.90-7.87 (m, 1H), 7.67 (d, J=8.2 Hz,2H), 7.58 (d, J=8.5 Hz, 2H), 6.99-6.95 (m, 1H), 6.55 (s, 1H), 4.73 (s,2H), 3.63-3.57 (m, 4H), 3.11-3.07 (m, 2H), 2.93-2.89 (m, 2H).

Example 52:[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

Step A.2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol

To solution of5-oxo-1-(3-trifluoromethyl-pyridin-2-yl)-azepane-4-carboxylic acid ethylester (3.0 g, 9.09 mmol) in EtOH (40 mL) was added NaOEt (1.97 g, 29.1mmol) and thiourea (1.1 g, 13.6 mmol). The mixture was heated at refluxfor 12 h. The mixture was cooled, treated with MeI (0.74 mL, 11.8 mmol)drop-wise, and stirred at rt for 1 h. The mixture was concentrated andthe residue was dissolved in water and acidified to pH=7 with HOAc (aprecipitate formed). The solid was filtered to give the title compound(3.3 g, >99%), which was used in the next step without furtherpurification.

Step B.4-Chloro-2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine

To a solution of2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol(1.8 g, 4.92 mmol) in CH₃CN (40 mL) was added POCl₃ (1.4 mL, 14.8 mmol).After 15 min at 80° C., the mixture was cooled to rt, diluted withEtOAc, and quenched slowly with satd. aq. NaHCO₃. The organic layer wasseparated, dried (MgSO₄), and concentrated. The crude residue waspurified (FCC) to give the title compound (1.6 g, 89%).

Step C

To a solution of4-chloro-2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine(830 mg, 2.22 mmol) in n-BuOH (5 mL) was added 4-trifluoromethylaniline(0.4 mL, 3.30 mmol). The mixture was heated in the microwave at 160° C.for 30 min, then was cooled to rt, quenched with satd. aq. NaHCO₃, andextracted with EtOAc. The combined organic layers were dried (MgSO₄) andconcentrated. The residue was purified (FCC) to give the title compound(950 mg, 86%). MS (ESI): mass calcd. for C₂₂H₁₉F₆N₅S, 499.13; m/z found,500.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.69(d, J=8.6 Hz, 2H), 7.58 (d, J=9.1 Hz, 2H), 6.99-6.94 (m, 1H), 6.65 (s,1H), 3.66-3.62 (m, 2H), 3.60-3.56 (m, 2H), 3.21-3.16 (m, 2H), 2.99-2.94(m, 2H), 2.53 (s, 3H).

Example 53:[2-Methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

To a solution of[2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine(Example 52; 513 mg, 1.02 mmol) in CH₂Cl₂ (10 mL) was added m-CPBA (77%;480 mg, 2.22 mmol). After 2 h, the mixture was diluted with satd. aq.NaHCO₃ and extracted with CH₂Cl₂. The combined organic layers were dried(MgSO₄) and concentrated. The residue was purified (FCC; MeOH/CH₂Cl₂) toafford the title compound (500 mg, 92%). MS (ESI): mass calcd. forC₂₂H₁₉F₆N₅O₂S, 531.12; m/z found, 532.8 [M+H]⁺. ¹H NMR (CD₃OD):8.46-8.44 (m, 1H), 8.04-8.01 (m, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.66 (d,J=8.5 Hz, 2H), 7.15-7.11 (m, 1H), 3.60-3.54 (m, 4H), 3.37-3.31 (m, 2H),3.28-3.23 (m, 5H).

Example 54:N²-Phenyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

A solution of[2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine(Example 53; 30 mg, 0.06 mmol), aniline (8 mg, 0.09 mmol), andp-toluenesulfonic acid (21.3 mg, 0.11 mmol) in toluene (2 mL) was heatedat 125° C. for 12 h. The mixture was cooled and directly purified usingPreparative HPLC to give the title compound (20 mg, 67%). MS (ESI): masscalcd. for C₂₇H₂₂F₆N₆, 544.18; m/z found, 545.9 [M+H]⁺. ¹H NMR (CD₃OD):8.46-8.44 (m, 1H), 8.00-7.97 (m, 1H), 7.66-7.58 (m, 4H), 7.48 (s, 1H),7.45-7.42 (m, 2H), 7.24-7.19 (m, 2H), 7.16-7.11 (m, 2H), 3.63-3.59 (m,2H), 3.57-3.53 (m, 2H), 3.29-3.25 (m, 2H), 3.11-3.07 (m, 2H).

Example 55:N²-Cyclopropyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

The title compound was prepared using methods analogous to thosedescribed in Example 54, with n-butanol or t-amyl alcohol as thesolvent, in a sealed tube at 130° C., and without the addition ofp-toluenesulfonic acid.

Example 55B:N²-Cyclopropyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₂F₆N₆, 508.18; m/z found, 509.8 [M+H]⁺.¹H NMR (CD₃OD): 8.49-8.44 (m, 1H), 8.04 (d, J=7.7 Hz, 1H), 7.92 (s, 2H),7.69 (d, J=8.8 Hz, 2H), 7.18-7.13 (m, 1H), 3.66-3.61 (m, 2H), 3.59-3.54(m, 2H), 3.31-3.24 (m, 2H), 3.15-3.11 (m, 2H), 2.76-2.66 (m, 1H),0.94-0.86 (m, 2H), 0.69-0.64 (m, 2H).

The compounds in Examples 56-61 were prepared using methods analogous tothose described in Example 55.

Example 56:[2-Azetidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

Example 56B:[2-Azetidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₂F₆N₆, 508.18; m/z found, 509.8 [M+H]⁺.¹H NMR (CD₃OD): 8.47-8.45 (m, 1H), 8.05-8.02 (m, 1H), 7.85 (d, J=8.5 Hz,2H), 7.69 (d, J=8.8 Hz, 2H), 7.17-7.13 (m, 1H), 4.32-4.22 (m, 4H),3.64-3.60 (m, 2H), 3.57-3.53 (m, 2H), 3.26-3.22 (m, 2H), 3.13-3.09 (m,2H), 2.53-2.45 (m, 2H).

Example 57:1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperidine-4-carboxylicacid

Example 57B:1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperidine-4-carboxylicacid trifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₆F₆N₆O₂, 580.2; m/z found, 581.9 [M+H]⁺.¹H NMR (CD₃OD): 8.49-8.44 (m, 1H), 8.07-8.02 (m, 1H), 7.74-7.72 (m, 4H),7.18-7.13 (m, 1H), 4.30-4.22 (m, 2H), 3.65-3.61 (m, 2H), 3.58-3.54 (m,2H), 3.34-3.25 (m, 4H), 3.14-3.09 (m, 2H), 2.74-2.66 (m, 1H), 2.08-2.01(m, 2H), 1.80-1.68 (m, 2H).

Example 58:N²-(2-Piperidin-1-yl-ethyl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

Example 58B:N²-(2-Piperidin-1-yl-ethyl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₈H₃₁F₆N₇, 579.25; m/z found, 581.0 [M+H]⁺.¹H NMR (CD₃OD): 8.47-8.44 (m, 1H), 8.05-8.01 (m, 1H), 7.79-7.70 (m, 4H),7.18-7.12 (m, 1H), 3.76-3.71 (m, 2H), 3.64-3.59 (m, 2H), 3.57-3.52 (m,2H), 3.44-3.36 (m, 2H), 3.24-3.17 (m, 4H), 3.13-3.07 (m, 2H), 2.81-2.70(m, 2H), 1.82-1.32 (m, 6H).

Example 59:1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-4-ol

Example 59B:1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-4-oltrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆O, 552.21; m/z found, 553.9 [M+H]⁺.¹H NMR (CD₃OD): 8.47-8.43 (m, 1H), 8.05-8.00 (m, 1H), 7.75-7.68 (m, 4H),7.17-7.11 (m, 1H), 4.07-3.98 (m, 2H), 3.97-3.88 (m, 1H), 3.64-3.57 (m,2H), 3.56-3.42 (m, 4H), 3.32-3.25 (m, 2H), 3.13-3.06 (m, 2H), 1.98-1.87(m, 2H), 1.64-1.49 (m, 2H).

Example 60:[2-(4-Isopropyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

Example 60B:[2-(4-Isopropyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₈H₃₁F₆N₇, 579.25; m/z found, 581.0 [M+H]⁺.¹H NMR (CD₃OD): 8.47-8.44 (m, 1H), 8.05-8.01 (m, 1H), 7.73-7.71 (m, 4H),7.18-7.12 (m, 1H), 3.66-3.24 (m, 15H), 3.18-3.07 (m, 2H), 1.38 (d, J=6.3Hz, 6H).

Example 61:N²-(Tetrahydro-pyran-4-yl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

Example 61B:N²-(Tetrahydro-pyran-4-yl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoro-methyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆O, 552.21; m/z found, 553.9 [M+H]⁺.¹H NMR (CD₃OD): 8.48-8.45 (m, 1H), 8.06-8.03 (m, 1H), 7.77 (d, J=8.5 Hz,2H), 7.72 (d, J=8.8 Hz, 2H), 7.18-7.14 (m, 1H), 3.98-3.84 (m, 3H),3.64-3.60 (m, 2H), 3.58-3.54 (m, 2H), 3.43-3.35 (m, 2H), 3.21-3.17 (m,2H), 3.12-3.09 (m, 2H), 1.92-1.84 (m, 2H), 1.65-1.54 (m, 2H).

Example 62:[2-Methoxy-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

A solution of[2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine(Example 53; 44 mg, 0.08 mmol) and NaOMe (100 mg, 0.25 mmol) in MeOH(1.5 mL) was heated at 60° C. for 1 h. The mixture was cooled, acidifiedwith HOAc (3 drops), and directly purified using Preparative HPLC(conditions as in Example 54) to give the title compound (35 mg, 89%).MS (ESI): mass calcd. for C₂₂H₁₉F₆N₅O, 483.15; m/z found, 484.8 [M+H]⁺.¹H NMR (CDCl₃): 9.63 (s, 1H), 8.39 (d, J=3.3 Hz, 1H), 7.89 (d, J=7.7 Hz,1H), 7.73 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.06-7.02 (m, 1H),3.88 (s, 3H), 3.50-3.44 (m, 4H), 3.26-3.22 (m, 2H), 3.11-3.07 (m, 2H).

The following Examples 63-109 were prepared using methods analogous tothose described in the preceding examples.

Example 63:N⁴-(3,4-Dichloro-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₂H₂₁C₁₂F₃N₆, 496.12; m/z found, 497.8[M+H]⁺.

Example 63B:N⁴-(3,4-Dichloro-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.46 (dd, J=4.7, 1.4 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz,1H), 7.93-7.92 (m, 1H), 7.53-7.52 (m, 2H), 7.17-7.12 (m, 1H), 3.64-3.58(m, 2H), 3.56-3.52 (m, 2H), 3.32-3.29 (m, 2H), 3.22 (s, 6H), 3.11-3.06(m, 2H).

Example 64:N⁴-(4-Methoxy-3-trifluoromethyl-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₄H₂₄F₆N₆O, 526.19; m/z found, 527.9 [M+H]⁺.¹H NMR (CD₃OD): 8.42 (dd, J=4.7, 1.6 Hz, 1H), 8.13 (d, J=2.7 Hz, 1H),7.90 (dd, J=7.8, 1.8 Hz, 1H), 7.56 (dd, J=8.9, 2.7 Hz, 1H), 7.04-6.93(m, 2H), 6.35 (s, 1H), 3.94 (s, 3H), 3.66-3.57 (m, 4H), 3.16 (s, 6H),3.14-3.09 (m, 2H), 2.90-2.85 (m, 2H).

Example 65:2-{4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-2-methyl-propionitrile

MS (ESI): mass calcd. for C₂₆H₂₈F₃N₇, 495.24; m/z found, 496.9 [M+H]⁺.

Example 65B:2-{4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-2-methyl-propionitriletrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz,1H), 7.66-7.60 (m, 2H), 7.58-7.53 (m, 2H), 7.17-7.11 (m, 1H), 3.64-3.58(m, 2H), 3.56-3.51 (m, 2H), 3.30-3.25 (m, 2H), 3.18 (s, 3H), 3.11-3.06(m, 2H), 1.73 (s, 6H).

Example 66:(4-tert-Butyl-phenyl)-[2-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₃₀H₃₇F₃N₆, 538.30; m/z found, 540.0 [M+H]⁺.

Example 66B:(4-tert-Butyl-phenyl)-[2-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-aminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.46 (dd, J=4.7, 1.4 Hz, 1H), 8.04 (dd, J=7.8, 1.7 Hz,1H), 7.53-7.49 (m, 2H), 7.39-7.35 (m, 2H), 7.17-7.13 (m, 1H), 4.41 (s,2H), 3.65-3.60 (m, 4H), 3.33-3.31 (m, 2H), 3.23-3.18 (m, 2H), 1.80-1.69(m, 4H), 1.68-1.58 (m, 2H), 1.36 (s, 9H), 1.29-1.21 (m, 2H).

Example 67:(4-tert-Butyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₆H₃₀F₃N₅O, 485.24; m/z found, 468.9 [M+H]⁺.

Example 67B:(4-tert-Butyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-aminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.66 (d, J=8.9 Hz, 1H), 8.52 (s, 1H), 8.40 (dd, J=4.7,1.5 Hz, 1H), 7.93 (dd, J=8.9, 2.3 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.63 (s, 1H), 7.00-6.95 (m, 1H), 3.65-3.56 (m, 4H), 3.28-3.21 (m, 2H),3.09-3.03 (m, 2H), 2.63 (s, 3H).

Example 68:N⁴-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₄H₂₅F₃N₆O₂, 486.20; m/z found, 487.8 [M+H]⁺.

Example 68B:N⁴-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.46-8.44 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H),7.16-7.12 (m, 1H), 7.11 (d, J=2.4 Hz, 1H), 6.98 (dd, J=8.7, 2.5 Hz, 1H),6.84 (d, J=8.7 Hz, 1H), 4.25 (s, 4H), 3.62-3.58 (m, 2H), 3.55-3.51 (m,2H), 3.29-3.24 (m, 2H), 3.17 (s, 6H), 3.07-3.02 (m, 2H).

Example 69:[2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

MS (ESI): mass calcd. for C₂₁H₁₈F₆N₆, 468.15; m/z found, 469.8 [M+H]⁺.¹H NMR (CDCl₃): 8.66 (d, J=8.9 Hz, 1H), 8.52 (s, 1H), 8.40 (dd, J=4.7,1.5 Hz, 1H), 7.93 (dd, J=8.9, 2.3 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.63 (s, 1H), 7.00-6.95 (m, 1H), 3.65-3.56 (m, 4H), 3.28-3.21 (m, 2H),3.09-3.03 (m, 2H), 2.63 (s, 3H).

Example 70:N⁴-Benzyl-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₃H₂₅F₃N₆, 442.21; m/z found, 443.8 [M+H]⁺.

Example 70B:N⁴-Benzyl-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.40-8.38 (m, 1H), 8.00-7.97 (m, 1H), 7.34-7.26 (m, 4H),7.25-7.20 (m, 1H), 7.10-7.06 (m, 1H), 4.70 (s, 2H), 3.60-3.56 (m, 2H),3.54-3.50 (m, 2H), 3.26-3.20 (m, 2H), 3.15 (s, 6H), 2.97-2.93 (m, 2H).

Example 71:4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzenesulfonamide

MS (ESI): mass calcd. for C₂₂H₂₄F₃N₇O₂S, 507.17; m/z found, 508.8[M+H]⁺.

Example 71B:4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzenesulfonamidetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.47-8.45 (m, 1H), 8.04 (dd, J=7.8, 1.7 Hz, 1H),7.94-7.91 (m, 2H), 7.81-7.77 (m, 2H), 7.19-7.11 (m, 1H), 3.66-3.58 (m,2H), 3.58-3.52 (m, 1H), 3.34-3.29 (m, 2H), 3.21 (s, 6H), 3.13-3.10 (m,2H).

Example 72:N²,N²-Dimethyl-N⁴-(4-nitro-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₂H₂₂F₃N₇O₂, 473.18; m/z found, 474.8 [M+H]⁺.

Example 72B:N²,N²-Dimethyl-N⁴-(4-nitro-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.48-8.45 (m, 1H), 8.31-8.26 (m, 2H), 8.04 (dd, J=7.8,1.8 Hz, 1H), 7.92-7.87 (m, 2H), 7.19-7.12 (m, 1H), 3.66-3.59 (m, 2H),3.58-3.54 (m, 2H), 3.37-3.33 (m, 2H), 3.24 (s, 3H), 3.16-3.12 (m, 2H).

Example 73:N⁴-(3,4-Dichloro-benzyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₃H₂₃C₁₂F₃N₆, 510.13; m/z found, 511.1[M+H]⁺.

Example 73B:N⁴-(3,4-Dichloro-benzyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.40 (dd, J=4.7, 1.3 Hz, 1H), 7.99 (dd, J=7.8, 1.8 Hz,1H), 7.48-7.46 (m, 1H), 7.44 (s, 1H), 7.24 (dd, J=8.3, 2.0 Hz, 1H),7.12-7.06 (m, 1H), 4.65 (s, 2H), 3.61-3.55 (m, 2H), 3.54-3.49 (m, 2H),3.25-3.18 (m, 2H), 3.14 (s, 6H), 2.97-2.91 (m, 2H).

Example 74:[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine

MS (ESI): mass calcd. for C₂₁H₁₈F₆N₆S, 500.12; m/z found, 501.8 [M+H]⁺.

Example 74B:[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-aminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.84-8.81 (m, 1H), 8.35 (dd, J=8.0, 1.5 Hz, 1H), 8.19(s, 1H), 7.75-7.65 (m, 2H), 6.71 (d, J=9.0 Hz, 1H), 4.32-4.24 (m, 2H),3.90-3.84 (m, 2H), 3.30-3.23 (m, 2H), 2.98 (t, J=6.3 Hz, 2H), 2.32 (s,3H).

Example 75:[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine

MS (ESI): mass calcd. for C₂₁H₁₈F₆N₆S, 500.12; m/z found, 501.8 [M+H]⁺.

Example 75B:[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-aminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 9.00 (d, J=2.4 Hz, 1H), 8.46-8.43 (m, 1H), 8.36 (dd,J=8.6, 2.4 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H), 7.78 (d, J=8.6 Hz,1H), 7.16-7.10 (m, 1H), 3.56-3.48 (m, 4H), 3.20-3.10 (m, 4H), 2.50 (s,3H).

Example 76:[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₃H₂₁F₆N₅O, 497.17; m/z found, 489.3 [M+H]⁺.

Example 76B:[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.46-8.44 (m, 1H), 8.03 (dd, J=7.9, 1.7 Hz, 1H),7.79-7.68 (m, 4H), 7.18-7.11 (m, 1H), 4.57 (s, 2H), 3.68-3.59 (m, 4H),3.52 (s, 3H), 3.46-3.42 (m, 2H), 3.28-3.23 (m, 2H).

Example 77:4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester

MS (ESI): mass calcd. for C₂₄H₂₅F₃N₆O₂, 486.20; m/z found, 487.8 [M+H]⁺.

Example 77B:4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester trifluoroacetic acid salt

¹H NMR (CD₃OD): 8.47 (dd, J=4.7, 1.5 Hz, 1H), 8.08-8.04 (m, 2H), 8.04(d, J=1.8 Hz, 1H), 7.75-7.72 (m, 2H), 7.18-7.13 (m, 1H), 3.92 (s, 3H),3.64-3.60 (m, 2H), 3.58-3.53 (m, 2H), 3.32-3.29 (m, 2H), 3.22 (s, 6H),3.15-3.09 (m, 2H).

Example 78:4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitrile

MS (ESI): mass calcd. for C₂₃H₂₂F₃N₇, 453.19; m/z found, 454.8 [M+H]⁺.

Example 78B:4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitriletrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.46 (dd, J=4.7, 1.4 Hz, 1H), 8.04 (dd, J=7.8, 1.8 Hz,1H), 7.85-7.81 (m, 2H), 7.79-7.76 (m, 2H), 7.18-7.13 (m, 1H), 3.65-3.59(m, 2H), 3.57-3.52 (m, 2H), 3.34-3.32 (m, 2H), 3.23 (s, 6H), 3.15-3.09(m, 2H).

Example 79:N⁴-(4-Dimethylamino-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₄H₂₈F₃N₇, 471.24; m/z found, 472.2 [M+H]⁺.

Example 79B:N⁴-(4-Dimethylamino-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.46-8.43 (m, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H),7.82-7.76 (m, 2H), 7.62-7.58 (m, 2H), 7.17-7.10 (m, 1H), 3.64-3.57 (m,2H), 3.56-3.51 (m, 2H), 3.31-3.28 (m, 2H), 3.27 (s, 6H), 3.19 (s, 6H),3.12-3.06 (m, 2H).

Example 80:(3-Chloro-4-trifluoromethyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₃H₂₀ClF₆N₅O, 531.13; m/z found, 532.3[M+H]⁺.

Example 80B:(3-Chloro-4-trifluoromethyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-aminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.44 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz,1H), 7.44-7.38 (m, 2H), 7.16-7.10 (m, 1H), 6.96-6.91 (m, 2H), 3.80 (s,3H), 3.62-3.57 (m, 2H), 3.56-3.50 (m, 2H), 3.29-3.23 (m, 2H), 3.14 (s,3H), 3.08-3.02 (m, 2H).

Example 81:N⁴-(4-Methoxy-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₃H₂₅F₃N₆O, 458.20; m/z found, 459.8 [M+H]⁺.

Example 81B:N⁴-(4-Methoxy-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.44 (dd, J=4.8, 1.4 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz,1H), 7.44-7.38 (m, 2H), 7.16-7.10 (m, 1H), 6.96-6.91 (m, 2H), 3.80 (s,3H), 3.62-3.57 (m, 2H), 3.56-3.50 (m, 2H), 3.29-3.23 (m, 2H), 3.14 (s,3H), 3.08-3.02 (m, 2H).

Example 82:N⁴-Indan-2-yl-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₅H₂₇F₃N₆, 468.22; m/z found, 469.9 [M+H]⁺.

Example 82B:N⁴-Indan-2-yl-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.44-8.41 (m, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H),7.25-7.20 (m, 2H), 7.18-7.15 (m, 2H), 7.15-7.11 (m, 1H), 5.04-4.95 (m,1H), 3.60-3.54 (m, 2H), 3.47-3.43 (m, 2H), 3.42-3.35 (m, 2H), 3.24 (s,6H), 3.23-3.20 (m, 2H), 3.10-3.02 (m, 2H), 2.95-2.90 (m, 2H).

Example 83:[7-(5-Amino-3-methyl-pyridin-2-yl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₇F₃N₆, 456.22; m/z found, 455.2 [M−H]⁻.¹H NMR (CDCl₃): 7.79 (d, J=8.6 Hz, 2H), 7.67 (d, J=2.9 Hz, 1H), 7.58 (d,J=8.7 Hz, 2H), 6.90-6.85 (m, 1H), 6.69-6.65 (m, 1H), 3.46-3.37 (m, 2H),3.34-3.29 (m, 2H), 3.26-3.22 (m, 2H), 3.21-3.17 (m, 2H), 3.10-3.03 (m,1H), 2.96-2.90 (m, 2H), 2.27 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).

Example 84:[7-(2-Amino-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅, 441.21; m/z found, 442.2 [M+H]⁺.¹H NMR (CDCl₃): 7.44-7.33 (m, 2H), 7.17-7.09 (m, 2H), 6.89-6.81 (m, 2H),6.67-6.59 (m, 2H), 4.10-3.97 (m, 2H), 3.60-3.47 (m, 2H), 3.13-3.03 (m,2H), 3.02-2.92 (m, 1H), 2.90-2.85 (m, 2H), 1.28-1.26 (m, 6H).

Example 85:[2-Isopropyl-7-(2-nitro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₄F₃N₅O₂, 471.19; m/z found, 472.1 [M+H]⁺.¹H NMR (CDCl₃): 7.99 (dd, J=8.2, 1.5 Hz, 1H), 7.66-7.56 (m, 1H),7.42-7.35 (m, 2H), 7.34-7.28 (m, 2H), 6.67-6.51 (m, 2H), 4.22-4.02 (m,2H), 3.62-3.47 (m, 2H), 3.15-3.04 (m, 2H), 2.96-2.83 (m, 3H), 1.21 (d,J=6.9 Hz, 6H).

Example 86:[7-(3-Amino-pyridin-2-yl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₃H₂₅F₃N₆, 442.21; m/z found, 443.1 [M+H]⁺.¹H NMR (CDCl₃): 7.86-7.72 (m, 3H), 7.64-7.57 (m, 2H), 7.04-6.95 (m, 1H),6.90-6.85 (m, 1H), 6.71-6.67 (m, 1H), 3.89-3.77 (m, 2H), 3.47-3.40 (m,2H), 3.39-3.35 (m, 2H), 3.26-3.21 (m, 2H), 3.13-3.04 (m, 1H), 3.01-2.94(m, 2H), 1.36 (d, J=6.9 Hz, 6H).

Example 87:[2-Isopropyl-7-(3-methyl-5-nitro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₅F₃N₆O₂, 486.20; m/z found, 487.1 [M+H]⁺.¹H NMR (CDCl₃): 8.93 (d, J=2.6 Hz, 1H), 8.16-8.05 (m, 1H), 7.81 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.35-7.28 (m, 1H), 6.76-6.60 (m,1H), 4.04-3.90 (m, 2H), 3.89-3.82 (m, 2H), 3.35-3.22 (m, 2H), 3.12-3.02(m, 3H), 2.41 (s, 3H), 1.33 (d, J=6.9 Hz, 6H).

Example 88:[2-Isopropyl-7-(3-nitro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₃H₂₃F₃N₆O₂, 472.18; m/z found, 473.1 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.28 (m, 1H), 8.15-8.12 (m, 1H), 7.36-7.21 (m, 4H),6.84-6.69 (m, 1H), 3.81-3.67 (m, 4H), 3.47-3.37 (m, 2H), 3.36-3.30 (m,2H), 3.22-3.07 (m, 1H), 1.32 (d, J=6.9 Hz, 6H).

Example 89:N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-phenyl}-methanesulfonamide

MS (ESI): mass calcd. for C₂₅H₂₈F₃N₅O₂S, 519.19; m/z found, 520.1[M+H]⁺. ¹H NMR (CDCl₃): 9.03-8.84 (m, 1H), 7.63-7.54 (m, 1H), 7.43-7.37(m, 2H), 7.32-7.28 (m, 2H), 6.69-6.57 (m, 2H), 4.18-4.01 (m, 2H),3.65-3.52 (m, 2H), 3.13-2.97 (m, 3H), 2.93-2.84 (m, 4H), 1.31 (d, J=6.9Hz, 6H).

Example 90:4-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperazin-2-one

MS (ESI): mass calcd. for C₂₅H₂₃F₆N₇O, 551.19; m/z found, 552.9 [M+H]⁺.

Example 90B:4-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperazin-2-onetrifluoroacetic acid salt

¹H NMR (CDCl₃): 8.41 (dd, J=4.8, 1.4 Hz, 1H), 7.91 (dd, J=7.8, 1.8 Hz,1H), 7.70 (d, J=8.7 Hz, 2H), 7.61 (d, J=8.6 Hz, 2H), 7.34-7.31 (m, 1H),7.05-7.01 (m, 1H), 6.53-6.45 (m, 1H), 4.39-4.31 (m, 2H), 4.14-4.09 (m,2H), 3.65-3.57 (m, 4H), 3.57-3.52 (m, 2H), 3.40-3.31 (m, 2H), 3.02-2.90(m, 2H).

Example 91:(R)-1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-3-ol

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆O, 552.21; m/z found, 553.9 [M+H]⁺.

Example 91B:(R)-1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-3-oltrifluoroacetic acid salt

¹H NMR (CDCl₃): 8.42-8.38 (m, 1H), 7.89 (dd, J=7.8, 1.6 Hz, 1H),7.67-7.59 (m, 5H), 7.02 (dd, J=7.7, 4.8 Hz, 1H), 4.33-4.23 (m, 1H),4.20-4.11 (m, 1H), 4.08-4.00 (m, 1H), 3.63-3.49 (m, 5H), 3.39-3.33 (m,2H), 3.31-3.22 (m, 1H), 2.99-2.90 (m, 2H), 2.03-1.90 (m, 1H), 1.89-1.73(m, 2H), 1.58-1.49 (m, 1H).

Example 92:[2-(4-Methyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₆H₂₇F₆N₇, 551.22; m/z found, 552.9 [M+H]⁺.

Example 92B:[2-(4-Methyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminetrifluoroacetic acid salt

¹H NMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 7.87 (dd, J=7.8, 1.8 Hz,1H), 7.64 (d, J=8.6 Hz, 2H), 7.56 (d, J=8.7 Hz, 2H), 6.97-6.91 (m, 1H),6.52 (s, 1H), 3.83-3.75 (m, 4H), 3.62-3.53 (m, 4H), 3.13-3.04 (m, 2H),2.90-2.84 (m, 2H), 2.52-2.42 (m, 4H), 2.34 (s, 3H).

Example 93:N²-(2-Methoxy-ethyl)-N²-methyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₅H₂₆F₆N₆O, 540.21; m/z found, 541.3 [M+H]⁺.

Example 93B:N²-(2-Methoxy-ethyl)-N²-methyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.45 (dd, J=4.8, 1.3 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz,1H), 7.76 (d, J=8.6 Hz, 2H), 7.70 (d, J=8.7 Hz, 2H), 7.17-7.11 (m, 1H),3.78-3.76 (m, 2H), 3.64-3.59 (m, 2H), 3.59-3.52 (m, 4H), 3.21 (s, 3H),3.13-3.08 (m, 2H).

Example 94:(S)-1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-3-ol

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆O, 552.21; m/z found, 553.3 [M+H]⁺.

Example 94B:(S)-1-[4-(4-Trifluoromethyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl]-piperidin-3-oltrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz,1H), 7.77-7.68 (m, 4H), 7.14 (dd, J=7.6, 4.8 Hz, 1H), 3.88-3.76 (m, 2H),3.70-3.51 (m, 7H), 3.30-3.25 (m, 2H), 3.13-3.07 (m, 2H), 2.00-1.86 (m,2H), 1.74-1.50 (m, 2H), 1.36-1.24 (m, 1H).

Example 95:N²-Cyclopropylmethyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₅H₂₄F₆N₆, 522.20; m/z found, 523.3 [M+H]⁺.

Example 95B:N²-Cyclopropylmethyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.04-8.01 (m, 1H),7.81-7.67 (m, 4H), 7.16-7.11 (m, 1H), 3.65-3.51 (m, 4H), 3.26-3.13 (m,4H), 3.11-3.06 (m, 2H), 1.10-1.00 (m, 1H), 0.52-0.45 (m, 2H), 0.22-0.15(m, 2H).

Example 96:1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-ethanone

MS (ESI): mass calcd. for C₂₅H₂₆F₃N₅O, 469.21; m/z found, 470.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 8.00-7.95 (m, 2H), 7.87 (dd, J=7.8,1.8 Hz, 1H), 7.81-7.77 (m, 2H), 6.98-6.94 (m, 1H), 6.73 (s, 1H),3.68-3.57 (m, 4H), 3.25-3.21 (m, 2H), 3.10-3.03 (m, 1H), 3.02-2.96 (m,2H), 2.59 (s, 3H), 1.34 (d, J=6.9 Hz, 6H).

Example 97:4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitrile

MS (ESI): mass calcd. for C₂₄H₂₃F₃N₆, 452.19; m/z found, 453.1 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.38 (m, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H),7.85-7.81 (m, 2H), 7.66-7.61 (m, 2H), 7.00-6.95 (m, 1H), 6.72 (s, 1H),3.69-3.57 (m, 4H), 3.28-3.23 (m, 2H), 3.13-3.04 (m, 1H), 3.03-2.98 (m,2H), 1.34 (d, J=6.9 Hz, 6H).

Example 98:(3,4-Dichloro-benzyl)-[2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₂H₂₀Cl₂F₃N₅S, 513.08; m/z found, 514.0[M+H]⁺. ¹H NMR (CDCl₃): 8.38-8.34 (m, 1H), 7.88-7.84 (m, 1H), 7.43-7.38(m, 2H), 7.18-7.14 (m, 1H), 6.96-6.91 (m, 1H), 5.05-4.97 (m, 1H), 4.66(d, J=5.7 Hz, 2H), 3.63-3.50 (m, 4H), 3.14-3.08 (m, 2H), 2.80-2.76 (m,2H), 2.44 (s, 3H).

Example 99:[2-Piperazin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₇, 537.21; m/z found, 538.2 [M+H]⁺.

Example 99B:[2-Piperazin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-aminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.47-8.44 (m, 1H), 8.03 (dd, J=7.8, 1.8 Hz, 1H),7.74-7.67 (m, 4H), 7.17-7.13 (m, 1H), 4.02-3.93 (m, 4H), 3.59-3.50 (m,4H), 3.35-3.21 (m, 6H), 3.13-3.07 (m, 2H).

Example 100:[2-Thiomorpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₅H₂₄F₆N₆S, 554.17; m/z found, 555.2 [M+H]⁺.¹H NMR (CDCl₃): 8.44-8.41 (m, 1H), 7.91 (dd, J=7.8, 1.8 Hz, 1H),7.67-7.57 (m, 4H), 7.02-6.96 (m, 1H), 6.56 (s, 1H), 4.20-4.08 (m, 4H),3.68-3.57 (m, 4H), 3.16-3.08 (m, 2H), 2.95-2.89 (m, 2H), 2.71-2.66 (m,4H).

Example 101:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅O₂S, 559.15; m/z found, 560.1[M+H]⁺.

Example 101B:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-aminetrifluoroacetic acid salt

¹H NMR (CD₃OD): 8.44-8.42 (m, 1H), 8.02-7.94 (m, 3H), 7.88-7.84 (m, 2H),7.14-7.09 (m, 1H), 3.83-3.76 (m, 1H), 3.69-3.60 (m, 6H), 3.29-3.22 (m,2H), 1.32-1.27 (m, 6H).

Example 102:[2-(4-Benzyl-piperazin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₃₂H₃₁F₆N₇, 627.25; m/z found, 628.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.38 (m, 1H), 7.88 (dd, J=7.8, 1.9 Hz, 1H),7.66-7.61 (m, 2H), 7.57-7.53 (m, 2H), 7.39-7.28 (m, 5H), 6.98-6.93 (m,1H), 6.51 (s, 1H), 3.82-3.76 (m, 4H), 3.63-3.55 (m, 6H), 3.12-3.07 (m,2H), 2.91-2.86 (m, 2H), 2.54-2.49 (m, 4H).

Example 103:4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester

MS (ESI): mass calcd. for C₂₅H₂₆F₃N₅O₂, 485.20; m/z found, 486.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 8.07-8.02 (m, 2H), 7.89 (dd, J=7.8,1.8 Hz, 1H), 7.80-7.75 (m, 2H), 6.99-6.95 (m, 1H), 6.71 (s, 1H), 3.92(s, 3H), 3.68-3.59 (m, 4H), 3.27-3.22 (m, 2H), 3.11-3.03 (m, 1H),3.02-2.98 (m, 2H), 1.35 (d, J=6.9 Hz, 6H).

Example 104:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethylsulfanyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅S, 527.16; m/z found, 528.1 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H),7.81-7.77 (m, 2H), 7.65-7.61 (m, 2H), 6.99-6.95 (m, 1H), 6.65 (s, 1H),3.70-3.58 (m, 4H), 3.27-3.22 (m, 2H), 3.12-3.03 (m, 1H), 3.02-2.97 (m,2H), 1.34 (d, J=6.9 Hz, 6H).

Example 105:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-pyrimidin-4-yl-amine

MS (ESI): mass calcd. for C₂₁H₂₂F₃N₇, 429.19; m/z found, 430.1 [M+H]⁺.¹H NMR (CDCl₃): 8.83-8.81 (m, 1H), 8.60 (d, J=5.9 Hz, 1H), 8.58-8.55 (m,1H), 8.42-8.40 (m, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.51 (s, 1H),7.01-6.97 (m, 1H), 3.65-3.56 (m, 4H), 3.29-3.25 (m, 2H), 3.17-3.10 (m,1H), 3.08-3.04 (m, 2H), 1.38 (d, J=6.9 Hz, 6H).

Example 106:[2-Pyrrolidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₅H₂₄F₆N₆, 522.20; m/z found, 523.1 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.38 (m, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.82-7.77 (m, 2H), 7.59-7.54 (m, 2H), 6.97-6.92 (m, 1H), 6.55 (s, 1H),3.64-3.53 (m, 8H), 3.13-3.08 (m, 2H), 2.91-2.87 (m, 2H), 2.02-1.94 (m,4H).

Example 107:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-pyrimidin-2-yl-amine

MS (ESI): mass calcd. for C₂₁H₂₂F₃N₇, 429.19; m/z found, 430.1 [M+H]⁺.¹H NMR (CDCl₃): 8.45 (d, J=4.8 Hz, 2H), 8.43-8.41 (m, 1H), 7.88 (dd,J=7.8, 1.8 Hz, 1H), 7.36 (s, 1H), 7.00-6.95 (m, 1H), 6.85-6.83 (m, 1H),3.65-3.58 (m, 2H), 3.55-3.50 (m, 2H), 3.35-3.30 (m, 2H), 3.14-3.06 (m,1H), 2.93-2.88 (m, 2H), 1.33 (d, J=6.9 Hz, 6H).

Example 108:[2-(3,4-Dichloro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₅H₂₆Cl₂F₃N₅, 523.15; m/z found, 524.1[M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.38 (d, J=8.2 Hz, 1H), 7.32 (d, J=2.0 Hz, 1H), 7.06 (dd, J=8.1, 2.0 Hz,1H), 6.96-6.92 (m, 1H), 4.68-4.63 (m, 1H), 3.80-3.70 (m, 2H), 3.61-3.57(m, 4H), 3.18-3.13 (m, 2H), 3.03-2.95 (m, 1H), 2.95-2.89 (m, 2H),2.72-2.68 (m, 2H), 1.32 (d, J=6.8 Hz, 6H).

Example 109:(3,4-Dichloro-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₃H₂₂Cl₂F₃N₅, 495.12; m/z found, 496.1[M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.38 (m, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.89(dd, J=7.8, 1.8 Hz, 1H), 7.43-7.37 (m, 2H), 6.99-6.95 (m, 1H), 6.50 (s,1H), 3.69-3.57 (m, 4H), 3.26-3.21 (m, 2H), 3.10-3.01 (m, 1H), 2.98-2.94(m, 2H), 1.34 (d, J=6.9 Hz, 6H).

The following compounds in Examples 110-114 are prepared according tothe procedures described above.

Example 110:N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-pyridin-3-yl}-methanesulfonamide

Example 111:N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-phenyl}-methanesulfonamide

Example 112:2-{4-[2-Azetidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol

Example 113:2-{4-[2-Azepan-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol

Example 114:N²-(2-Dimethylamino-ethyl)-N²-methyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamineIntermediate C: 5-Trifluoromethyl-pyrazin-2-ylamine

The title compound was prepared using known procedures (See: U.S. Pat.No. 4,160,834).

Intermediate D: 6-Chloro-5-trifluoromethyl-pyridin-2-ylamine

The title compound was prepared from2,6-dichloro-3-trifluoromethyl-pyridine using methods analogous toIntermediate C (See: Hirokawa et al. Chem. Pharm. Bull. 2001, 49(12),1621; Katritzky, A. R. et al. J. Org. Chem. 1997, 62, 6412).

Intermediate E: 6-Methoxy-5-trifluoromethyl-pyridin-2-ylamine

The title compound was prepared as described by Hirokawa et al. Chem.Pharm. Bull. 2001, 49(12), 1621 and WO 2006/081388.

Intermediate F: 1-Methyl-1,2,3,4-tetrahydro-quinolin-7-ylamine

The title compound was prepared using methods analogous to thosedescribed by Hamann, L. G. et al. J. Med. Chem. 1998, 41, 623 andHiguchi, R. I. et al. Bioorg. Med. Chem. Lett. 1999, 9, 1335.

Intermediate G: 1,4,4-Trimethyl-1,2,3,4-tetrahydro-quinolin-7-ylamine

The title compound was prepared using methods analogous to IntermediateF.

Intermediate H: 2-(4-Amino-phenyl)-2-methyl-propionic acid methyl ester

Step A: 2-Methyl-2-(4-nitrophenyl)-propionic acid methyl ester

To a solution of 2-methyl-2-(4-nitrophenyl)-propionic acid (1.0014 g,4.76 mmol) in 10% MeOH/benzene (20 mL) was added dropwise(trimethylsilyl)-diazomethane (2.0 M in hexanes, 3.5 mL, 7.0 mmol). Thereaction mixture was stirred at rt until evolution of N₂ ceased (<5 min)and then concentrated. The crude residue was purified (FCC) to give thetitle compound (937.6 mg, 88%).

Step B

To a solution of 2-methyl-2-(4-nitrophenyl)-propionic acid methyl ester(932.2 mg, 4.16 mmol) and ammonium formate (1.58 g, 25.1 mmol) in MeOHwas added Pd/C (10%, 441.2 mg, 0.414 mmol). The reaction mixture wasstirred at rt until gas evolution ceased, then filtered through a plugof diatomaceous earth and concentrated. The residue was redissolved inH₂O and extracted with EtOAc. The organic layers were combined, dried,and concentrated to provide the title compound which was used withoutfurther purification.

The following Examples 115-126 were prepared using methods analogous tothose described in Example 1, substituting the appropriate amidines inStep A and amines in Step E.

Example 115:N-{[4-Chloro-3-(trifluoromethyl)phenyl]methyl}-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₄ClF₆N₅, 543.16; m/z found, 544.1 [M+H]⁺.¹H NMR (CDCl₃): 8.37-8.35 (m, 1H), 7.87-7.84 (m, 1H), 7.73-7.71 (m, 1H),7.49-7.43 (m, 2H), 6.95-6.91 (m, 1H), 5.05-4.99 (m, 1H), 4.72 (d, J=5.8Hz, 2H), 3.63-3.55 (m, 4H), 3.18-3.12 (m, 2H), 2.98-2.89 (m, 1H),2.82-2.77 (m, 2H), 1.22 (d, J=6.9 Hz, 6H).

Example 116:2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₄F₆N₆, 510.20; m/z found, 511.1 [M+H]⁺.¹H NMR (CDCl₃): 8.75-8.73 (m, 1H), 8.38-8.35 (m, 1H), 7.89-7.84 (m, 2H),7.62 (d, J=8.1 Hz, 1H), 6.95-6.92 (m, 1H), 5.11-5.07 (m, 1H), 4.81 (d,J=5.8 Hz, 2H), 3.62-3.55 (m, 4H), 3.18-3.13 (m, 2H), 2.97-2.87 (m, 1H),2.84-2.79 (m, 2H), 1.20 (d, J=6.9 Hz, 6H).

Example 117:2-(1-Methylethyl)-N-{[4-(trifluoromethyl)phenyl]methyl}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₅, 509.20; m/z found, 510.1 [M+H]⁺.¹H NMR (CDCl₃): 8.37-8.35 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.58(d, J=8.1 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 6.95-6.91 (m, 1H), 5.00-4.95(m, 1H), 4.79 (d, J=5.7 Hz, 2H), 3.63-3.56 (m, 4H), 3.17-3.13 (m, 2H),2.98-2.88 (m, 1H), 2.82-2.77 (m, 2H), 1.23 (d, J=6.9 Hz, 6H).

Example 118:N-[2-(2-Fluorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₇F₄N₅, 473.22; m/z found, 474.1 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.36 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.24-7.17 (m, 2H), 7.10-7.02 (m, 2H), 6.95-6.91 (m, 1H), 4.73-4.69 (m,1H), 3.78-3.74 (m, 2H), 3.59-3.56 (m, 4H), 3.14-3.12 (m, 2H), 3.01-2.93(m, 3H), 2.69-2.67 (m, 2H), 1.30 (d, J=6.9 Hz, 6H).

Example 119:N-[2-(2-Bromophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₇BrF₃N₅, 534.14; m/z found, 536.1 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.36 (m, 1H), 7.85 (dd, J=7.8, 1.8 Hz, 1H),7.57-7.54 (m, 1H), 7.25-7.20 (m, 2H), 7.11-7.07 (m, 1H), 6.94-6.90 (m,1H), 4.70-4.67 (m, 1H), 3.82-3.77 (m, 2H), 3.60-3.54 (m, 4H), 3.16-3.08(m, 4H), 3.02-2.93 (m, 1H), 2.71-2.68 (m, 2H), 1.31 (d, J=6.9 Hz, 6H).

Example 120:N-[(2,6-Dichlorophenyl)methyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₄Cl₂F₃N₅, 509.14; m/z found, 510.1[M+H]⁺. ¹H NMR (CDCl₃): 8.36-8.34 (m, 1H), 7.84 (dd, J=7.8, 1.8 Hz, 1H),7.33 (d, J=8.0 Hz, 2H), 7.20-7.16 (m, 1H), 6.93-6.90 (m, 1H), 5.05 (d,J=5.5 Hz, 2H), 4.95-4.92 (m, 1H), 3.61-3.54 (m, 4H), 3.16-3.10 (m, 2H),3.01-2.94 (m, 1H), 2.75-2.72 (m, 2H), 1.31 (d, J=6.9 Hz, 6H).

Example 121:N-[(2-Chlorophenyl)methyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₅ClF₃N₅, 475.18; m/z found, 477.1 [M+H]⁺.¹H NMR (CD₃OD): 8.40-8.38 (m, 1H), 8.02-7.98 (m, 1H), 7.42-7.39 (m, 1H),7.29-7.20 (m, 3H), 7.10-7.06 (m, 1H), 3.67-3.64 (m, 2H), 3.61-3.57 (m,2H), 3.31-3.26 (m, 4H), 3.09-3.06 (m, 2H), 3.01-2.92 (m, 1H), 1.20 (d,J=6.8 Hz, 6H).

Example 122:N-[4-(1,1-Dimethylethyl)cyclohexyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₈F₃N₅, 489.31; m/z found, 490.2 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.36 (m, 1H), 7.85 (dd, J=7.8, 1.8 Hz, 1H),6.94-6.90 (m, 1H), 4.34-4.31 (m, 1H), 3.96-3.86 (m, 1H), 3.64-3.54 (m,4H), 3.14-3.09 (m, 2H), 2.96-2.89 (m, 1H), 2.74-2.69 (m, 2H), 2.25-2.18(m, 2H), 1.88-1.80 (m, 2H), 1.27 (d, J=6.9 Hz, 6H), 1.25-0.95 (m, 5H),0.89 (s, 9H).

Example 123:N-[2-(3-Chlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₇ClF₃N₅, 489.19; m/z found, 490.1 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.36 (m, 1H), 7.85 (dd, J=7.8, 1.8 Hz, 1H),7.25-7.20 (m, 3H), 7.11-7.08 (m, 1H), 6.95-6.90 (m, 1H), 4.68-4.60 (m,1H), 3.77-3.73 (m, 2H), 3.61-3.55 (m, 4H), 3.18-3.11 (m, 2H), 3.02-2.88(m, 3H), 2.69-2.64 (m, 2H), 1.31 (d, J=6.9 Hz, 6H).

Example 124:N-[2-(4-Chlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₇ClF₃N₅, 489.19; m/z found, 490.4 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.36 (m, 1H), 7.86-7.85 (m, 1H), 7.29-7.26 (m, 2H),7.15-7.13 (m, 2H), 6.95-6.92 (m, 1H), 4.64-4.61 (m, 1H), 3.73 (dd,J=13.2, 6.7 Hz, 2H), 3.61-3.54 (m, 4H), 3.16-3.11 (m, 2H), 3.00-2.93 (m,1H), 2.91 (t, J=7.1 Hz, 2H), 2.68-2.65 (m, 2H), 1.31 (d, J=6.9 Hz, 6H).

Example 125:N-[2-(2,6-Dichlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₆Cl₂F₃N₅, 523.15; m/z found, 524.4[M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.29 (d, J=8.0 Hz, 2H), 7.11-7.07 (m, 1H), 6.95-6.91 (m, 1H), 4.79-4.75(m, 1H), 3.85 (dd, J=6.8, 12.8 Hz, 2H), 3.62-3.54 (m, 4H), 3.30 (t,J=13.8, 6.9 Hz, 2H), 3.14-3.10 (m, 2H), 2.96-2.90 (m, 1H), 2.74-2.70 (m,2H), 1.28 (d, J=6.9 Hz, 6H).

Example 126:2-(1-Methylethyl)-N-{2-[2-(methyloxy)phenyl]ethyl}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₃₀F₃N₅O, 485.24; m/z found, 486.5 [M+H]⁺.¹H NMR (CDCl₃): 8.37-8.35 (m, 1H), 7.85 (dd, J=7.8, 1.7 Hz, 1H),7.25-7.20 (m, 1H), 7.16-7.14 (m, 1H), 6.94-6.87 (m, 3H), 5.03-4.99 (m,1H), 3.86 (s, 3H), 3.72-3.68 (m, 2H), 3.58-3.56 (m, 4H), 3.13-3.10 (m,2H), 2.97-2.90 (m, 3H), 2.69-2.65 (m, 2H), 1.29 (d, J=6.9 Hz, 6H).

Example 127:N,N-Dimethyl-4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzamide

The title compound was prepared using methods analogous to thosedescribed in Example 1, using isobutyramidine in Step A,4-amino-N,N-dimethyl-benzamide in Step E, and substituting t-amylalcohol for n-butanol in Step E. MS (ESI): mass calcd. for C₂₆H₂₉F₃N₆O,498.24; m/z found, 499.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.89(dd, J=7.8, 1.8 Hz, 1H), 7.75-7.72 (m, 2H), 7.47-7.44 (m, 2H), 6.99-6.95(m, 1H), 6.63 (s, 1H), 3.72-3.60 (m, 4H), 3.27-3.21 (m, 2H), 3.16-3.02(m, 7H), 3.00-2.97 (m, 2H), 1.34 (d, 6.9 Hz, 6H).

The following Examples 128-175 were prepared using methods analogous tothose described in Example 46, substituting the appropriate amidines inStep A and amines in Step E.

Example 128:N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₂ClF₆N₅, 529.14; m/z found, 530.1 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.38 (m, 1H), 8.16 (d, J=2.0 Hz, 1H), 7.88 (dd,J=7.8, 1.8 Hz, 1H), 7.62 (d, 8.7 Hz, 1H), 7.55-7.52 (m, 1H), 6.99-6.95(m, 1H), 6.66 (s, 1H),

Example 129:2-Methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanenitrile

MS (ESI): mass calcd. for C₂₇H₂₉F₃N₆, 494.24; m/z found, 495.2 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.38 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.74-7.70 (m, 2H), 7.45-7.42 (m, 2H), 6.97-6.93 (m, 1H), 6.53 (s, 1H),3.67-3.60 (m, 4H), 3.24-3.21 (m, 2H), 3.06-3.01 (m, 1H), 2.98-2.94 (m,2H), 1.74 (s, 6H), 1.32 (d, J=6.9 Hz, 6H).

Example 130:4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzoicacid

MS (ESI): mass calcd. for C₂₄H₂₄F₃N₅O₂, 471.19; m/z found, 472.1 [M+H]⁺.¹H NMR (CD₃OD): 8.46-8.43 (m, 1H), 8.07-8.01 (m, 3H), 7.76-7.72 (m, 2H),7.16-7.12 (m, 1H), 3.68-3.58 (m, 4H), 3.34-3.30 (m, 2H), 3.24-3.20 (m,2H), 3.12-3.05 (m, 1H), 1.31 (d, J=6.8 Hz, 6H).

Example 131:N-Biphenyl-4-yl-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₂₈F₃N₅, 503.23; m/z found, 504.5 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.89-7.86 (m, 1H), 7.77-7.74 (m, 2H),7.64-7.58 (m, 4H), 7.46-7.42 (m, 2H), 7.35-7.30 (m, 1H), 6.97-6.93 (m,1H), 6.57 (s, 1H), 3.70-3.65 (m, 2H), 3.64-3.60 (m, 2H), 3.24-3.20 (m,2H), 3.08-3.01 (m, 1H), 2.99-2.96 (m, 2H), 1.34 (d, J=6.9 Hz, 6H).

Example 132:N-(4-Cyclohexylphenyl)-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₄F₃N₅, 509.27; m/z found, 510.5 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.60-7.57 (m, 2H), 7.20-7.16 (m, 2H), 6.95-6.92 (m, 1H), 6.44 (s, 1H),3.68-3.58 (m, 4H), 3.22-3.18 (m, 2H), 3.05-2.97 (m, 1H), 2.95-2.91 (m,2H), 2.52-2.44 (m, 1H), 1.93-1.80 (m, 4H), 1.78-1.70 (m, 2H), 1.46-1.36(m, 4H), 1.31 (d, J=6.9 Hz, 6H).

Example 133:2-(1-Methylethyl)-N-(4-piperidin-1-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₃₃F₃N₆, 510.27; m/z found, 511.5 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.88-7.85 (m, 1H), 7.53-7.49 (m, 2H),6.97-6.91 (m, 3H), 6.35 (s, 1H), 3.68-3.57 (m, 4H), 3.22-3.17 (m, 2H),3.15-3.09 (m, 4H), 3.03-2.95 (m, 1H), 2.93-2.88 (m, 2H), 1.76-1.71 (m,4H), 1.60-1.54 (m, 2H), 1.29 (d, J=6.9 Hz, 6H).

Example 134:2-(1-Methylethyl)-N-(4-morpholin-4-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆O, 512.25; m/z found, 513.5 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.57-7.53 (m, 2H), 6.95-6.90 (m, 3H), 6.37 (s, 1H), 3.90-3.86 (m, 4H),3.67-3.59 (m, 4H), 3.21-3.17 (m, 2H), 3.15-3.12 (m, 4H), 3.03-2.96 (m,1H), 2.93-2.90 (m, 2H), 1.29 (d, J=6.9 Hz, 6H).

Example 135:2-(1-Methylethyl)-N-[4-(methylsulfanyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅S, 473.19; m/z found, 474.4 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.63-7.60 (m, 2H), 7.30-7.26 (m, 2H), 6.97-6.92 (m, 1H), 6.46 (s, 1H),3.69-3.57 (m, 4H), 3.24-3.18 (m, 2H), 3.06-2.97 (m, 1H), 2.95-2.92 (m,2H), 2.49 (s, 3H), 1.31 (d, J=6.9 Hz, 6H).

Example 136:2-(1-Methylethyl)-N-(4-nitrophenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₃H₂₃F₃N₆O₂, 472.18; m/z found, 473.4 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 8.26-8.23 (m, 2H), 7.89-7.84 (m, 3H),6.98-6.95 (m, 1H), 6.85 (s, 1H), 3.66-3.63 (m, 2H), 3.61-3.59 (m, 2H),3.27-3.23 (m, 2H), 3.13-3.05 (m, 1H), 3.04-2.99 (m, 2H), 1.34 (d, J=6.9Hz, 6H).

Example 137:2-(1-Methylethyl)-N-[4-(1-methylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₃₀F₃N₅, 469.25; m/z found, 470.2 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.60-7.57 (m, 2H), 7.23-7.18 (m, 2H), 6.96-6.92 (m, 1H), 6.45 (s, 1H),3.69-3.58 (m, 4H), 3.24-3.17 (m, 2H), 3.06-2.97 (m, 1H), 2.96-2.85 (m,3H), 1.32 (d, J=6.9 Hz, 6H), 1.26 (d, J=6.8, 6H).

Example 138:2-(1,1-Dimethylethyl)-N-[4-(1,1-dimethylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₃₄F₃N₅, 497.28; m/z found, 498.2 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.86 (d, J=7.8, 1.8 Hz, 1H),7.64-7.60 (m, 2H), 7.39-7.33 (m, 2H), 6.96-6.91 (m, 1H), 6.43 (s, 1H),3.71-3.58 (m, 4H), 3.24-3.18 (m, 2H), 2.96-2.92 (m, 2H), 1.38 (s, 9H),1.33 (s, 9H).

Example 139:2-(1,1-Dimethylethyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₅, 509.20; m/z found, 510.1 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.90-7.86 (m, 1H), 7.80 (d, J=8.5 Hz,2H), 7.59 (d, J=8.6 Hz, 2H), 6.98-6.93 (m, 1H), 6.62 (s, 1H), 3.69-3.64(m, 2H), 3.63-3.58 (m, 2H), 3.27-3.21 (m, 2H), 3.02-2.95 (m, 2H), 1.38(s, 9H).

Example 140:N-[3-Fluoro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₂F₇N₅, 513.18; m/z found, 514.1 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.38 (m, 1H), 8.05-8.00 (m, 1H), 7.88 (dd, J=7.8,1.8 Hz, 1H), 7.54-7.49 (m, 1H), 7.27-7.25 (m, 1H), 6.99-6.94 (m, 1H),6.71 (s, 1H), 3.69-3.57 (m, 4H), 3.27-3.21 (m, 2H), 3.12-3.03 (m, 1H),3.01-2.95 (m, 2H), 1.34 (d, J=6.9 Hz, 6H).

Example 141:N-(2,3-Dihydro-1H-inden-5-yl)-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminehydrochloride salt

MS (ESI): mass calcd. for C₂₆H₂₈F₃N₅, 467.23; m/z found, 468.2 [M+H]⁺.¹H NMR (CD₃OD): 8.46-8.43 (m, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H),7.40-7.38 (m, 1H), 7.26-7.21 (m, 2H), 7.14-7.11 (m, 1H), 3.66-3.63 (m,2H), 3.61-3.57 (m, 2H), 3.19-3.14 (m, 2H), 3.06-2.97 (m, 1H), 2.96-2.90(m, 6H), 2.15-2.08 (m, 2H), 1.26 (d, J=6.8 Hz, 6H).

Example 142:2-(1-Methylethyl)-N-[4-(1,3-oxazol-5-yl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₃N₆O, 494.20; m/z found, 495.1 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.90-7.86 (m, 2H), 7.78-7.75 (m, 2H),7.66-7.62 (m, 2H), 7.30 (s, 1H), 6.98-6.93 (m, 1H), 6.61 (s, 1H),3.70-3.58 (m, 4H), 3.26-3.19 (m, 2H), 3.10-2.94 (m, 3H), 1.33 (d, J=6.9Hz, 6H).

Example 143:N-[4-(1,1-Dimethylethyl)-3-nitrophenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆O₂, 528.24; m/z found, 529.2 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 8.10 (d, J=2.4 Hz, 1H), 7.87 (dd,J=7.8, 1.8 Hz, 1H), 7.53 (dd, J=8.8, 2.4 Hz, 1H), 7.47 (d, J=8.8 Hz,1H), 6.99-6.94 (m, 1H), 6.57 (s, 1H), 3.68-3.56 (m, 4H), 3.26-3.17 (m,2H), 3.07-2.99 (m, 1H), 2.98-2.93 (m, 2H), 1.41 (s, 9H), 1.31 (d, J=6.9Hz, 6H).

Example 144:2-Furan-2-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₁₉F₆N₅O, 519.15; m/z found, 520.1 [M+H]⁺.¹H NMR (CDCl₃): 8.32-8.31 (m, 1H), 7.81 (dd, J=7.8, 1.8 Hz, 1H), 7.73(d, J=8.6 Hz, 2H), 7.56 (d, J=8.6 Hz, 2H), 7.53-7.52 (m, 1H), 7.14-7.11(m, 1H), 6.92-6.87 (m, 1H), 6.68 (s, 1H), 6.49-6.46 (m, 1H), 3.64-3.52(m, 4H), 3.30-3.23 (m, 2H), 3.01-2.95 (m, 2H).

Example 145:N-[4-(1,1-Dimethylethyl)phenyl]-2-furan-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₂₈F₃N₅O, 507.22; m/z found, 508.2 [M+H]⁺.¹H NMR (CDCl₃): 8.33-8.31 (m, 1H), 7.80 (dd, J=7.8, 1.9 Hz, 1H),7.54-7.50 (m, 3H), 7.35-7.31 (m, 2H), 7.13-7.11 (m, 1H), 6.89-6.85 (m,1H), 6.48 (s, 1H), 6.46-6.44 (m, 1H), 3.63-3.53 (m, 4H), 3.27-3.21 (m,2H), 2.96-2.90 (m, 2H), 1.27 (s, 9H).

Example 146:2-Furan-3-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₁₉F₆N₅O, 519.15; m/z found, 520.1 [M+H]⁺.¹H NMR (CDCl₃): 8.33-8.31 (m, 1H), 8.10-8.08 (m, 1H), 7.81 (dd, J=7.8,1.8 Hz, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.7 Hz, 2H), 7.41-7.39(m, 1H), 6.94-6.92 (m, 1H), 6.91-6.87 (m, 1H), 6.62 (s, 1H), 3.64-3.52(m, 4H), 3.24-3.17 (m, 2H), 2.99-2.93 (m, 2H).

Example 147:N-[4-(1,1-Dimethylethyl)phenyl]-2-furan-3-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₂₈F₃N₅O, 507.22; m/z found, 508.2 [M+H]⁺.¹H NMR (CDCl₃): 8.33-8.31 (m, 1H), 8.09-8.07 (m, 1H), 7.80 (dd, J=7.8,1.8 Hz, 1H), 7.52-7.48 (m, 2H), 7.39-7.37 (m, 1H), 7.34-7.30 (m, 2H),6.95-6.93 (m, 1H), 6.89-6.86 (m, 1H), 6.42 (s, 1H), 3.64-3.52 (m, 4H),3.21-3.14 (m, 2H), 2.95-2.88 (m, 2H), 1.28 (s, 9H).

Example 148:Benzo[1,2,5]thiadiazol-5-yl-[2-isopropyl-7-(3-trifluoromethyl-pyridin-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₃H₂₂F₃N₇S, 485.16; m/z found, 486.1 [M+H]⁺.¹H NMR (CDCl₃): 8.56-8.53 (m, 1H), 8.34-8.31 (m, 1H), 7.85 (d, J=9.4 Hz,1H), 7.81 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (dd, J=9.4, 2.2 Hz, 1H),6.91-6.87 (m, 1H), 6.68 (s, 1H), 3.63-3.59 (m, 2H), 3.57-3.54 (m, 2H),3.21-3.16 (m, 2H), 3.07-2.99 (m, 1H), 2.98-2.95 (m, 2H), 1.30 (d, J=6.9Hz, 6H).

Example 149:2-(2-Thienyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₁₉F₆N₅S, 535.13; m/z found, 536.1 [M+H]⁺.¹H NMR (CDCl₃): 8.33-8.31 (m, 1H), 7.86-7.83 (m, 1H), 7.81 (dd, J=7.8,1.8 Hz, 1H), 7.76 (d, J=8.5 Hz, 2H), 7.57 (d, J=8.6 Hz, 2H), 7.37-7.34(m, 1H), 7.06-7.04 (m, 1H), 6.91-6.87 (m, 1H), 6.64 (s, 1H), 3.65-3.53(m, 4H), 3.26-3.20 (m, 2H), 3.00-2.94 (m, 2H).

Example 150:2-(3-Thienyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₁₉F₆N₅S, 535.13; m/z found, 536 [M+H]⁺. ¹HNMR (CDCl₃): 8.40-8.38 (m, 1H), 8.20-8.18 (m, 1H), 7.90-7.86 (m, 1H),7.84-7.78 (m, 3H), 7.65-7.63 (m, 2H), 7.36-7.34 (m, 1H), 6.99-6.94 (m,1H), 6.69 (s, 1H), 3.72-3.60 (m, 4H), 3.35-3.26 (m, 2H), 3.08-3.02 (m,2H).

Example 151:2-(1-Methylethyl)-N-(4-methylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminehydrochloride salt

MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅, 441.21; m/z found, 442.2 [M+H]⁺.¹H NMR (CD₃OD): 8.46-8.44 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H),7.42-7.39 (m, 2H), 7.24-7.22 (m, 2H), 7.17-7.13 (m, 1H), 3.68-3.58 (m,4H), 3.35-3.30 (m, 2H), 3.21-3.15 (m, 2H), 3.10-3.00 (m, 1H), 2.37 (s,3H), 1.26 (d, J=6.8 Hz, 6H).

Example 152:2-(1-Methylethyl)-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆O₂S, 560.22; m/z found, 561.1[M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.90-7.85 (m, 3H), 7.82-7.78(m, 2H), 6.99-6.94 (m, 1H), 6.74 (s, 1H), 3.66-3.57 (m, 4H), 3.29-3.21(m, 6H), 3.11-2.97 (m, 3H), 1.81-1.74 (m, 4H), 1.34 (d, J=6.9 Hz, 6H).

Example 153:2-(2-Methyl-1,3-thiazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₂₀F₆N₆S, 550.14; m/z found, 551.2 [M+H]⁺.¹H NMR (CD₃OD): 8.48-8.44 (m, 1H), 8.34 (s, 1H), 8.07-8.02 (m, 1H),7.89-7.86 (m, 2H), 7.82-7.77 (m, 2H), 7.18-7.13 (m, 1H), 3.72-3.62 (m,4H), 3.56-3.53 (m, 2H), 3.33-3.30 (m, 2H), 2.84 (s, 3H).

Example 154:N,N-Dimethyl-4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzenesulfonamide

MS (ESI): mass calcd. for C₂₅H₂₉F₃N₆O₂S, 534.20; m/z found, 535.3[M+H]⁺. ¹H NMR (CDCl₃): 8.42-8.40 (m, 1H), 7.92-7.89 (m, 3H), 7.78-7.75(m, 2H), 7.01-6.96 (m, 1H), 6.77 (s, 1H), 3.69-3.60 (m, 4H), 3.29-3.24(m, 2H), 3.14-3.06 (m, 1H), 3.04-3.00 (m, 2H), 2.74 (s, 6H), 1.36 (d,6.9 Hz, 6H).

Example 155:N-[2-Fluoro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₂F₇N₅, 513.18; m/z found, 514.2 [M+H]⁺.¹H NMR (CDCl₃): 8.93-8.88 (m, 1H), 8.42-8.40 (m, 1H), 7.89 (dd, J=7.8,1.8 Hz, 1H), 7.49-7.46 (m, 1H), 7.41-7.38 (m, 1H), 7.00-6.97 (m, 2H),3.70-3.67 (m, 2H), 3.63-3.60 (m, 2H), 3.28-3.25 (m, 2H), 3.13-3.06 (m,1H), 3.04-3.01 (m, 2H), 1.36 (d, J=6.9 Hz, 6H).

Example 156:1-[4-({2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone

MS (ESI): mass calcd. for C₂₇H₂₉F₃N₆O, 510.24; m/z found, 511.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.98-7.95 (m, 2H), 7.88 (dd, J=7.8,1.8 Hz, 1H), 7.66-7.64 (m, 2H), 6.98-6.94 (m, 1H), 6.60 (s, 1H),3.81-3.74 (m, 4H), 3.64-3.55 (m, 4H), 3.14-3.08 (m, 2H), 2.92-2.86 (m,2H), 2.60 (s, 3H), 1.71-1.60 (m, 6H).

Example 157:N-[3-Fluoro-4-(trifluoromethyl)phenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₇N₆, 554.20; m/z found, 555.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.84-7.81 (m, 1H), 7.50 (t, J=8.4 Hz, 1H), 7.18-7.14 (m, 1H), 6.98-6.95(m, 1H), 6.57 (s, 1H), 3.81-3.73 (m, 4H), 3.63-3.55 (m, 4H), 3.13-3.07(m, 2H), 2.91-2.85 (m, 2H), 1.73-1.60 (m, 6H).

Example 158:N,N-Dimethyl-4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzenesulfonamide

MS (ESI): mass calcd. for C₂₇H₃₂F₃N₇O₂S, 575.23; m/z found, 576.3[M+H]⁺. ¹H NMR (CDCl₃): 8.42-8.40 (m, 1H), 7.90-7.88 (m, 1H), 7.76-7.72(m, 4H), 6.98-6.95 (m, 1H), 6.60 (s, 1H), 3.79-3.75 (m, 4H), 3.61-3.56(m, 4H), 3.12-3.08 (m, 2H), 2.92-2.87 (m, 2H), 2.73 (s, 6H), 1.72-1.63(m, 6H).

Example 159:N-[4-(1,1-Dimethylethyl)-3-nitrophenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₄F₃N₇O₂, 569.27; m/z found, 570.3 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 8.08 (d, J=2.5 Hz, 1H), 7.88 (dd,J=7.8, 1.8 Hz, 1H), 7.45 (d, J=8.8 Hz, 1H), 7.31-7.28 (m, 1H), 6.97-6.93(m, 1H), 6.42 (s, 1H), 3.77-3.71 (m, 4H), 3.64-3.55 (m, 4H), 3.11-3.06(m, 2H), 2.88-2.83 (m, 2H), 1.71-1.59 (m, 6H), 1.41 (s, 9H).

Example 160:N-[4-(Methylsulfanyl)phenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₉F₃N₆S, 514.21; m/z found, 515.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.39 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.52-7.47 (m, 2H), 7.30-7.26 (m, 2H), 6.97-6.92 (m, 1H), 6.32 (s, 1H),3.77-3.70 (m, 4H), 3.65-3.56 (m, 4H), 3.11-3.06 (m, 2H), 2.87-2.84 (m,2H), 2.50 (s, 3H), 1.69-1.57 (m, 6H).

Example 161:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine

MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆, 496.26; m/z found, 497.3 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.36 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.20(d, J=2.0 Hz, 1H), 6.96-6.86 (m, 2H), 6.68 (dd, J=8.0, 2.1 Hz, 1H), 6.40(s, 1H), 3.72-3.56 (m, 4H), 3.27-3.16 (m, 4H), 3.05-2.90 (m, 6H), 2.74(t, J=6.4 Hz, 2H), 2.02-1.94 (m, 2H), 1.32 (d, J=6.9 Hz, 6H).

Example 162:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine

MS (ESI): mass calcd. for C₂₉H₃₅F₃N₆, 524.29; m/z found, 525.3 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.23(d, J=2.2 Hz, 1H), 7.14 (d, J=8.3 Hz, 1H), 6.97-6.92 (m, 1H), 6.78 (dd,J=8.2, 2.2 Hz, 1H), 6.43 (s, 1H), 3.70-3.60 (m, 4H), 3.29-3.25 (m, 2H),3.23-3.20 (m, 2H), 3.06-3.00 (m, 1H), 2.98-2.93 (m, 5H), 1.80-1.77 (m,2H), 1.35 (d, J=6.9 Hz, 6H), 1.30 (s, 6H).

Example 163:(1-Methyl-1,2,3,4-tetrahydro-quinolin-7-yl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-aminehydrochloride salt

MS (ESI): mass calcd. for C₂₉H₃₄F₃N₇, 537.28; m/z found, 538.3 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.89 (dd, J=7.8, 1.7 Hz, 1H),7.02-6.98 (m, 1H), 6.97-6.94 (m, 2H), 6.75-6.72 (m, 1H), 6.66-6.62 (m,1H), 4.09-3.78 (m, 6H), 3.69-3.61 (m, 4H), 3.31-3.25 (m, 2H), 2.92-2.87(m, 5H), 2.80-2.75 (m, 2H), 2.04-1.97 (m, 2H), 1.74-1.66 (m, 6H).

Example 164:[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-aminehydrochloride salt

MS (ESI): mass calcd. for C₃₁H₃₈F₃N₇, 565.31; m/z found, 566.3 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.90-7.88 (m, 1H), 7.19 (d, J=8.2 Hz,1H), 7.02-6.93 (m, 2H), 6.78-6.69 (m, 2H), 4.10-3.90 (m, 4H), 3.87-3.80(m, 2H), 3.69-3.61 (m, 4H), 3.33-3.26 (m, 2H), 2.94-2.87 (m, 5H),1.82-1.77 (m, 2H), 1.75-1.67 (m, 6H), 1.31 (s, 6H).

Example 165:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-pyrrolidin-1-yl-pyridin-3-yl)-amine

MS (ESI): mass calcd. for C₂₆H₃₀F₃N₇, 497.25; m/z found, 498.3 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 8.20 (d, J=2.6 Hz, 1H), 7.88 (dd,J=7.8, 1.8 Hz, 1H), 7.85 (dd, J=9.0, 2.7 Hz, 1H), 6.98-6.94 (m, 1H),6.41 (d, J=9.0 Hz, 1H), 6.21 (s, 1H), 3.70-3.66 (m, 2H), 3.64-3.62 (m,2H), 3.50-3.48 (m, 4H), 3.23-3.18 (m, 2H), 2.99-2.92 (m, 3H), 2.07-2.01(m, 4H), 1.27 (d, J=6.9 Hz, 6H).

Example 166:(2-Fluoro-4-trifluoromethyl-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₇N₆, 554.25; m/z found, 555.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.36 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.84-7.78 (m, 1H), 7.48 (t, J=8.4 Hz, 1H), 7.16-7.11 (m, 1H), 6.97-6.91(m, 1H), 6.55 (s, 1H), 3.78-3.70 (m, 4H), 3.61-3.52 (m, 4H), 3.11-3.05(m, 2H), 2.88-2.83 (m, 2H), 1.72-1.56 (m, 6H).

Example 167:2-Pyridin-4-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₀F₆N₆, 530.17; m/z found, 531.5 [M+H]⁺.¹H NMR (MeOD): 8.90 (d, J=6.6 Hz, 2H), 8.81 (d, J=6.7 Hz, 1H), 8.45-8.42(m, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H), 7.87 (d, J=8.5 Hz, 2H), 7.69 (d,J=8.6 Hz, 2H), 7.12 (dd, J=7.7, 4.9 Hz, 1H), 3.62-3.56 (m, 4H),3.42-3.37 (m, 2H), 3.29-3.25 (m, 2H).

Example 168:N-[4-(1,1-Dimethylethyl)phenyl]-2-pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₉H₂₉F₃N₇, 518.24; m/z found, 519.5 [M+H]⁺.¹H NMR (MeOD): 8.89 (d, J=6.6 Hz, 2H), 8.72 (d, J=6.7 Hz, 2H), 8.44 (dd,J=4.7, 1.4 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H), 7.58-7.54 (m, 2H),7.47-7.44 (m, 2H), 7.12 (dd, J=7.8, 4.8 Hz, 1H), 3.63-3.57 (m, 4H),3.40-3.35 (m, 2H), 3.26-3.21 (m, 2H), 1.36 (s, 9H).

Example 169:N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₁₉ClF₆N₆, 564.13; m/z found, 565.4 [M+H]⁺.¹H NMR (CDCl₃): 8.76 (d, J=5.1 Hz, 2H), 8.40 (d, J=3.7 Hz, 1H), 8.22 (d,J=5.3 Hz, 2H), 8.09 (s, 1H), 7.91-7.87 (m, 1H), 7.70 (d, J=8.8 Hz, 1H),7.58 (d, J=9.0 Hz, 1H), 7.01-6.95 (m, 1H), 6.81 (s, 1H), 3.75-3.61 (m,4H), 3.41-3.32 (m, 2H), 3.13-3.06 (m, 2H).

Example 170:2-Pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₁₉F₆N₇, 531.16; m/z found, 532.1 [M+H]⁺.¹H NMR (CDCl₃): 9.04 (d, J=2.3 Hz, 1H), 8.90 (d, J=6.4 Hz, 2H), 8.73 (d,J=6.4 Hz, 2H), 8.43-8.41 (m, 1H), 8.21 (dd, J=8.5, 2.3 Hz, 1H), 7.94(dd, J=7.8, 1.6 Hz, 1H), 7.79 (d, J=8.6 Hz, 1H), 7.33 (s, 1H), 7.06-7.02(m, 1H), 3.77-3.72 (m, 2H), 3.71-3.65 (m, 2H), 3.43-3.38 (m, 2H),3.25-3.19 (m, 2H).

Example 171:N-[4-(1,1-Dimethylethyl)phenyl]-2-pyridin-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₉H₂₉F₃N₆, 518.24; m/z found, 519.5 [M+H]⁺.¹H NMR (MeOD): 8.84-8.82 (m, 1H), 8.45 (dd, J=4.7, 1.5 Hz, 1H),8.27-8.23 (m, 1H), 8.09-8.00 (m, 2H), 7.72-7.65 (m, 1H), 7.54 (s, 4H),7.16-7.12 (m, 1H), 3.72-3.63 (m, 4H), 3.57-3.52 (m, 2H), 3.30-3.26 (m,2H), 1.39 (s, 9H).

Example 172:2-Pyridin-2-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminele 1 trifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₀F₆N₆, 530.17; m/z found, 531.5 [M+H]⁺.¹H NMR (MeOD): 8.88-8.81 (m, 1H), 8.47-8.44 (m, 1H), 8.34-8.31 (m, 1H),8.16 (dt, J=7.8, 1.6 Hz, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H), 7.86 (d,J=8.6 Hz, 2H), 7.80 (d, J=8.6 Hz, 2H), 7.77-7.73 (m, 1H), 7.17-7.12 (m,1H), 3.71-3.64 (m, 4H), 3.60-3.55 (m, 2H), 3.35-3.31 (m, 2H).

Example 173:N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-pyridin-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₁₉ClF₆N₆, 564.13; m/z found, 565.1 [M+H]⁺.¹H NMR (MeOD): 8.92-8.82 (m, 1H), 8.47-8.44 (m, 1H), 8.44-8.41 (m, 1H),8.27 (dt, J=7.8, 1.6 Hz, 1H), 8.05-8.01 (m, 2H), 7.88 (d, J=8.7 Hz, 1H),7.84-7.80 (m, 2H), 7.17-7.13 (m, 1H), 3.70-3.62 (m, 4H), 3.60-3.55 (m,2H), 3.35-3.31 (m, 2H).

Example 174: Methyl2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate

MS (ESI): mass calcd. for C₂₈H₃₂F₃N₅O₂, 527.25; m/z found, 528.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.39 (m, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.69-7.65 (m, 2H), 7.35-7.31 (m, 2H), 6.98-6.94 (m, 1H), 6.51 (s, 1H),3.70-3.60 (m, 7H), 3.25-3.20 (m, 2H), 3.08-3.00 (m, 1H), 2.98-2.95 (m,2H), 1.61 (s, 6H), 1.34 (d, J=6.9 Hz, 6H).

Example 175: Methyl2-methyl-2-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate

MS (ESI): mass calcd. for C₃₀H₃₅F₃N₆O₂, 568.27; m/z found, 569.3 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.39 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.56-7.52 (m, 2H), 7.32-7.28 (m, 2H), 6.97-6.92 (m, 1H), 6.36 (s, 1H),3.78-3.72 (m, 4H), 3.67 (s, 3H), 3.64-3.56 (m, 4H), 3.11-3.05 (m, 2H),2.88-2.83 (m, 2H), 1.70-1.58 (m, 12H).

Example 176:2-Pyridin-3-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

A microwave vial containing[2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine(Example 53; 100 mg, 0.20 mmol), Pd₂(dba)₃ (7.3 mg, 0.008 mmol),tri-(2-furyl)phosphine (7.4 mg, 0.032 mmol), copper(I)thiophene-2-carboxylate (49 mg, 0.260 mmol), and 3-pyridyl boronic acid(27 mg, 0.22 mmol) was sealed and evacuated under N₂. Upon completeflushing with N₂, THF (3 mL) was added. The reaction mixture was stirredat 50° C. for 18 h. The reaction mixture was filtered through a plug ofdiatomaceous earth, concentrated, and purified directly usingPreparative HPLC (conditions as in Example 54) to give the titlecompound (40 mg, 40%). MS (ESI): mass calcd. for C₂₆H₂₀F₆N₆, 530.17; m/zfound, 531.2 [M+H]⁺. ¹H NMR (MeOD): 9.32-9.28 (m, 1H), 8.54-8.36 (m,1H), 8.03 (dd, J=7.8, 1.6 Hz, 1H), 7.88 (d, J=8.0 Hz, 2H), 7.73-7.69 (m,1H), 7.17-7.11 (m, 1H), 3.64-3.57 (m, 4H), 3.42-3.37 (m, 2H), 3.29-3.24(m, 2H).

Example 177:2-[4-({2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol

To a solution of methylmagnesium bromide (170 mL of a 3.0 M solution inEt₂O, 0.51 mmol) in THF at 0° C. was added a solution of1-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone(Example 156; 59.8 mg, 0.117 mmol) in THF. The solution was allowed towarm to rt over 1 h, and stirred at rt for an additional 5 min. Thereaction mixture was then quenched with satd. aq. NH₄Cl and extractedwith EtOAc. The organic layers were combined, dried, and concentrated.The crude residue was purified (FCC) to give the title compound (51 mg,83%). MS (ESI): mass calcd. for C₂₈H₃₃F₃N₆O, 526.27; m/z found, 527.3[M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.55-7.51 (m, 2H), 7.46-7.41 (m, 2H), 6.94-6.90 (m, 1H), 6.35 (s, 1H),3.77-3.69 (m, 4H), 3.63-3.53 (m, 4H), 3.10-3.03 (m, 2H), 2.87-2.80 (m,2H), 1.70 (s, 1H), 1.66-1.60 (m, 6H), 1.54 (s, 6H).

Example 178:2-[4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol

The title compound was prepared using methods analogous to thosedescribed in Example 167, starting with1-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone(Example 96). MS (ESI): mass calcd. for C₂₆H₃₀F₃N₅O, 485.24; m/z found,486.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.87 (dd, J=7.8, 1.8Hz, 1H), 7.68-7.63 (m, 2H), 7.48-7.45 (m, 2H), 6.97-6.92 (m, 1H), 6.50(s, 1H), 3.69-3.58 (m, 4H), 3.25-3.17 (m, 2H), 3.08-2.98 (m, 1H),2.98-2.92 (m, 2H), 1.61 (s, 6H), 1.32 (d, J=6.9 Hz, 6H).

Example 179:1,1,1-Trifluoro-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol

The title compound was prepared using methods analogous to thosedescribed in Example 167, starting with2,2,2-trifluoro-1-{4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-ethanone(prepared analogously to Example 1). MS (ESI): mass calcd. forC₂₆H₂₇F₆N₅O, 539.21; m/z found, 540.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.40(m, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.77-7.73 (m, 2H), 7.59-7.54 (m,2H), 6.99-6.95 (m, 1H), 6.58 (s, 1H), 3.71-3.60 (m, 4H), 3.27-3.21 (m,2H), 3.09-3.02 (m, 1H), 3.01-2.96 (m, 2H), 2.42 (s, 1H), 1.82 (s, 3H),1.34 (d, J=6.9 Hz, 6H).

Example 180:1,1,1-Trifluoro-2-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol

The title compound was prepared using methods analogous to thosedescribed in Example 167, starting with2,2,2-trifluoro-1-{4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-ethanone(prepared analogously to Example 1). MS (ESI): mass calcd. forC₂₈H₃₀F₆N₆O, 580.24; m/z found, 581.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.38(m, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.63-7.60 (m, 2H), 7.54-7.51 (m,2H), 6.97-6.92 (m, 1H), 6.42 (s, 1H), 3.80-3.71 (m, 4H), 3.66-3.56 (m,4H), 3.12-3.06 (m, 2H), 2.90-2.84 (m, 2H), 2.37 (s, 1H), 1.81 (s, 3H),1.70-1.59 (m, 6H).

Example 181:2-Methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-1-ol

To a solution of methyl2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate(Example 174, 73 mg, 0.14 mmol) in THF was added LiAlH₄ (14.2 mg, 0.374mmol). After stirring at rt for 4 h, the reaction mixture was quenchedwith satd. aq. Na₂SO₄. The reaction mixture was then filtered through aplug of diatomaceous earth and concentrated. The crude residue waspurified (FCC) to give the title compound (45.4 mg, 66%). MS (ESI): masscalcd. for C₂₇H₃₂F₃N₅O, 499.26; m/z found, 500.3 [M+H]⁺. ¹H NMR (CDCl₃):8.41-8.39 (m, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.70-7.66 (m, 2H),7.40-7.36 (m, 2H), 6.98-6.94 (m, 1H), 6.51 (s, 1H), 3.70-3.60 (m, 6H),3.26-3.20 (m, 2H), 3.08-3.00 (m, 1H), 2.98-2.94 (m, 2H), 1.37 (s, 6H),1.34 (d, 6.9 Hz, 6H).

Example 182:1-[4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanol

To a solution of1-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone(Example 96; 37 mg, 0.079 mmol) in MeOH was added NaBH₄ (4.1 mg, 0.11mmol). The mixture was stirred at rt for 4 h, then concentrated. Theresidue was redissolved in water and extracted with EtOAc. The organiclayers were combined, dried, and concentrated. The crude residue waspurified (FCC) to give the title compound (32.1 mg, 86%). MS (ESI): masscalcd. for C₂₅H₂₈F₃N₅O, 471.22; m/z found, 472.2 [M+H]⁺. ¹H NMR (CDCl₃):8.40-8.38 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H), 7.67-7.64 (m, 2H),7.38-7.34 (m, 2H), 6.97-6.92 (m, 1H), 6.51 (s, 1H), 4.93-4.88 (m, 1H),3.69-3.60 (m, 4H), 3.24-3.18 (m, 2H), 3.06-2.98 (m, 1H), 2.98-2.94 (m,2H), 1.76 (d, J=3.6 Hz, 1H), 1.52 (d, J=6.4 Hz, 3H), 1.31 (d, J=6.9 Hz,6H).

Example 183:2,2,2-Trifluoro-1-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanol

The title compound was prepared using methods analogous to thosedescribed in Example 172, starting with2,2,2-trifluoro-1-{4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-ethanone(prepared analogously to Example 1). MS (ESI): mass calcd. forC₂₅H₂₅F₆N₅O, 525.20; m/z found, 526.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.32-8.30(m, 1H), 7.80 (dd, J=7.8, 1.8 Hz, 1H), 7.69-7.65 (m, 2H), 7.40-7.36 (m,2H), 6.90-6.86 (m, 1H), 6.51 (s, 1H), 4.97-4.91 (m, 1H), 3.59-3.56 (m,2H), 3.54-3.51 (m, 2H), 3.17-3.12 (m, 2H), 3.00-2.92 (m, 1H), 2.90-2.87(m, 2H), 2.66-2.60 (m, 1H), 1.26-1.23 (m, 6H).

Example 184:2-Methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoicacid

To a solution of methyl2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate(Example 174; 63 mg, 0.12 mmol) in 1:2 THF:H₂O (3 mL:6 mL) was addedlithium hydroxide monohydrate (8.0 mg, 0.19 mmol). The mixture washeated at 60° C. for 5 h. The THF was removed under reduced pressure,and the resulting solution was acidified to neutral pH with 10% aq. HCl.The solution was then extracted with EtOAc. The organic layers werecombined, dried, and concentrated. The crude residue was purified (FCC)to give the title compound (37 mg, 60%). MS (ESI): mass calcd. forC₂₇H₃₀F₃N₅O₂, 513.24; m/z found, 514.1 [M+H]⁺. ¹H NMR (CD₃OD): 8.45-8.42(m, 1H), 8.01 (dd, J=7.9, 1.7 Hz, 1H), 7.69-7.63 (m, 2H), 7.38-7.33 (m,2H), 7.13-7.09 (m, 1H), 3.57-3.50 (m, 4H), 3.21-3.16 (m, 2H), 3.13-3.08(m, 2H), 3.01-2.93 (m, 1H), 1.57 (s, 6H), 1.28 (d, J=6.9 Hz, 6H).

Example 185:4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzoicacid trifluoroacetic acid salt

The title compound was prepared using methods analogous to thosedescribed in Example 184, starting with methyl4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzoate(Example 103) and purified using preparative HPLC. MS (ESI): mass calcd.for C₂₄H₂₄F₃N₅O₂, 471.19; m/z found, 472.1 [M+H]⁺. ¹H NMR (CD₃OD):8.46-8.43 (m, 1H), 8.07-8.01 (m, 3H), 7.76-7.72 (m, 2H), 7.16-7.12 (m,1H), 3.68-3.58 (m, 4H), 3.34-3.30 (m, 2H), 3.24-3.20 (m, 2H), 3.12-3.05(m, 1H), 1.31 (d, J=6.8 Hz, 6H).

Example 186:2-Methyl-2-[4-({2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoicacid

The title compound was prepared using methods analogous to thosedescribed in Example 184, starting with of methyl2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate(Example 174). MS (ESI): mass calcd. for C₂₉H₃₃F₃N₆O₂, 554.26; m/zfound, 555.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8,1.8 Hz, 1H), 7.56-7.52 (m, 2H), 7.37-7.32 (m, 2H), 6.95-6.90 (m, 1H),6.35 (s, 1H), 3.76-3.70 (m, 4H), 3.62-3.54 (m, 4H), 3.07-3.03 (m, 2H),2.85-2.80 (m, 2H), 1.68-1.56 (m, 12H).

The following Examples 187-190 were prepared using methods analogous tothose described in Example 17, substituting the appropriate amidines inStep A and amines in Step E.

Example 187:2-(1-Methylethyl)-N-(5-methylpyrazin-2-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminehydrochloride salt

MS (ESI): mass calcd. for C₂₂H₂₄F₃N₇, 443.20; m/z found, 444.1 [M+H]⁺.¹H NMR (CD₃OD): 9.15-9.13 (m, 1H), 8.44-8.41 (m, 1H), 8.39-8.38 (m, 1H),8.00 (dd, J=7.8, 1.6 Hz, 1H), 7.15-7.09 (m, 1H), 3.66-3.53 (m, 4H),3.39-3.33 (m, 2H), 3.27-3.21 (m, 2H), 3.19-3.09 (m, 1H), 2.55 (s, 3H),1.32 (d, J=6.8 Hz, 6H).

Example 188:N-[6-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminehydrochloride salt

MS (ESI): mass calcd. for C₂₃H₂₁ClF₆N₆, 530.14; m/z found, 531.2 [M+H]⁺.¹H NMR (CDCl₃): 8.57-8.52 (m, 1H), 8.47-8.44 (m, 1H), 8.18 (d, J=8.6 Hz,1H), 8.12 (s, 1H), 7.95-7.91 (m, 1H), 7.02-7.07 (m, 1H), 4.09-3.99 (m,1H), 3.93-3.84 (m, 2H), 3.71-3.64 (m, 4H), 3.21-3.13 (m, 2H), 1.48 (d,J=6.7 Hz, 6H).

Example 189:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-methoxy-5-trifluoromethyl-pyridin-2-yl)-aminehydrochloride salt

MS (ESI): mass calcd. for C₂₄H₂₄F₆N₆O, 526.19; m/z found, 527.2 [M+H]⁺.¹H NMR (CD₃OD): 8.48-8.45 (m, 1H), 8.10-8.02 (m, 2H), 7.89-7.85 (m, 1H),7.19-7.14 (m, 1H), 4.06 (s, 3H), 3.71-3.66 (m, 2H), 3.64-3.59 (m, 2H),3.44-3.39 (m, 2H), 3.34-3.28 (m, 2H), 3.24-3.17 (m, 1H), 1.41-1.39 (m,6H).

Example 190:2-Pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₁₉F₆N₇, 531.16; m/z found, 532.5 [M+H]⁺.¹H NMR (MeOD): 8.96-8.92 (m, 2H), 8.92-8.89 (m, 2H), 8.66-8.63 (m, 1H),8.44 (dd, J=4.8, 1.4 Hz, 1H), 8.30 (d, J=8.8 Hz, 1H), 8.12 (dd, J=9.0,2.3 Hz, 1H), 8.02 (dd, J=7.9, 1.8 Hz, 1H), 7.15-7.10 (m, 1H), 3.64-3.55(m, 4H), 3.48-3.40 (m, 2H), 3.30-3.27 (m, 2H).

Examples 191-192 were prepared using methods analogous to thosedescribed in Example 17, substituting the appropriate amidines in StepA, amines in Step E, and substituting Pd₂(dba)₃ (5 mol %) for Pd(OAc)₂and 1,2,3,4,5-pentaphenyl-1′-(di-tbutylphosphino)ferrocene (Qphos, 10mol %) for DCPB.

Example 191:[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine

MS (ESI): mass calcd. for C₂₂H₂₁F₆N₇, 497.18; m/z found, 498.2 [M+H]⁺.¹H NMR (CDCl₃): 10.02-10.01 (m, 1H), 8.56-8.55 (m, 1H), 8.40-8.38 (m,1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.56 (s, 1H), 7.01-6.96 (m, 1H),3.67-3.55 (m, 4H), 3.31-3.24 (m, 2H), 3.16-3.04 (m, 3H), 1.36 (d, J=6.9Hz, 6H).

Example 192:[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine

MS (ESI): mass calcd. for C₂₄H₂₄F₆N₈, 538.20; m/z found, 539.2 [M+H]⁺.¹H NMR (CDCl₃): 9.76-9.73 (m, 1H), 8.56-8.54 (m, 1H), 8.42-8.40 (m, 1H),7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.43 (s, 1H), 6.99-6.95 (m, 1H), 3.81-3.75(m, 4H), 3.62-3.53 (m, 4H), 3.15-3.09 (m, 2H), 2.98-2.92 (m, 2H),1.75-1.58 (m, 6H).

The following Examples 193-197 were prepared using methods analogous tothose described in Example 39, substituting the appropriatecarboximidamidines in Step A and amines in Step C.

Example 193:2-(4-Methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₆F₆N₈, 552.22; m/z found, 553.2 [M+H]⁺.¹H NMR (CDCl₃): 8.50-8.48 (m, 1H), 8.41-8.38 (m, 2H), 7.90-7.86 (m, 2H),7.44 (s, 1H), 6.97-6.94 (m, 1H), 3.86-3.79 (m, 4H), 3.58-3.52 (m, 4H),3.13-3.08 (m, 2H), 2.95-2.91 (m, 2H), 2.51-2.47 (m, 4H), 2.35 (s, 3H).

Example 194:2-Azepan-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₇F₆N₇, 551.22; m/z found, 552.2 [M+H]⁺.¹H NMR (CDCl₃): 8.80 (d, J=8.8 Hz, 1H), 8.49-8.48 (m, 1H), 8.40-8.38 (m,1H), 7.88-7.84 (m, 2H), 7.44 (s, 1H), 6.96-6.92 (m, 1H), 3.81-3.72 (m,4H), 3.59-3.52 (m, 4H), 3.12-3.08 (m, 2H), 2.94-2.90 (m, 2H), 1.84-1.78(m, 4H), 1.59-1.55 (m, 4H).

Example 195:N²-[2-(Dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₅H₂₈F₆N₈, 554.23; m/z found, 555.2 [M+H]⁺.¹H NMR (CDCl₃): 8.56 (d, J=8.9 Hz, 1H), 8.49-8.48 (m, 1H), 8.40-8.38 (m,1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H), 7.84-7.82 (m, 1H), 7.45 (s, 1H),6.96-6.94 (m, 1H), 3.79-3.73 (m, 2H), 3.57-3.52 (m, 4H), 3.19 (s, 3H),3.11-3.09 (m, 2H), 2.93-2.90 (m, 2H), 2.55-2.50 (m, 2H), 2.30 (s, 6H).

Example 196:N²-Methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₄H₂₅F₆N₇O, 541.20; m/z found, 542.1 [M+H]⁺.¹H NMR (CDCl₃): 8.55 (d, J=8.8 Hz, 1H), 8.49-8.48 (m, 1H), 8.40-8.39 (m,1H), 7.88-7.84 (m, 2H), 7.46 (s, 1H), 6.97-6.94 (m, 1H), 3.84-3.80 (m,2H), 3.64-3.61 (m, 2H), 3.56-3.53 (m, 4H), 3.38 (s, 3H), 3.23 (s, 3H),3.11-3.09 (m, 2H), 2.93-2.91 (m, 2H).

Example 197:2-Azetidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₃H₂₁F₆N₇, 509.18; m/z found, 510.5 [M+H]⁺.¹H NMR (MeOD): 8.69 (s, 1H), 8.47-8.42 (m, 1H), 8.41 (d, J=8.8 Hz, 1H),8.14 (dd, J=8.9, 2.3 Hz, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H), 7.16-7.11(m, 1H), 4.37-4.32 (m, 4H), 3.63-3.58 (m, 2H), 3.55-3.51 (m, 2H),3.29-3.24 (m, 2H), 3.15-3.10 (m, 2H), 2.57-2.48 (m, 2H).

The following Examples 198-201 were prepared using reduction methodsanalogous to those described in International Publication No.WO2005/117890:

Example 198:N-{2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}benzene-1,4-diaminetrifluoroacetic acid salt

The title compound was prepared from2-(1-methylethyl)-N-(4-nitrophenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 136). MS (ESI): mass calcd. for C₂₃H₂₅F₃N₆, 442.21; m/z found,443.1 [M+H]⁺. ¹H NMR (CD₃OD): 8.38-8.36 (m, 1H), 7.97-7.94 (m, 1H),7.59-7.53 (m, 2H), 7.27-7.19 (m, 2H), 7.10-7.06 (m, 1H), 3.60-3.51 (m,4H), 3.27-3.24 (m, 2H), 3.14-3.11 (m, 2H), 3.03-2.96 (m, 1H), 1.20 (d,J=6.8 Hz, 6H).

Example 199:4-(1,1-Dimethylethyl)-N1-{2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}benzene-1,3-diamine

The title compound was prepared fromN-[4-(1,1-dimethylethyl)-3-nitrophenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 143). MS (ESI): mass calcd. for C₂₇H₃₃F₃N₆, 498.27; m/z found,499.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.31-8.29 (m, 1H), 7.80-7.78 (m, 1H), 7.21(d, J=2.3 Hz, 1H), 7.10 (d, J=8.5 Hz, 1H), 6.87-6.84 (m, 1H), 6.82 (dd,J=8.5, 2.3 Hz, 1H), 6.31 (s, 1H), 3.82-3.70 (br s, 2H), 3.59-3.51 (m,4H), 3.16-3.10 (m, 2H), 3.02-2.91 (m, 1H), 2.87-2.82 (m, 2H), 1.35 (s,9H), 1.26 (d, J=6.9 Hz, 6H).

Example 200:4-(1,1-Dimethylethyl)-N1-{2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}benzene-1,3-diamine

The title compound was prepared fromN-[4-(1,1-dimethylethyl)-3-nitrophenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 159). MS (ESI): mass calcd. for C₂₉H₃₆F₃N₇, 539.30; m/z found,540.3 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.87 (dd, J=7.8, 1.8Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 7.08 (d, J=2.3 Hz, 1H), 6.95-6.91 (m,1H), 6.85 (dd, J=2.3, 8.5 Hz, 1H), 6.24 (s, 1H), 3.83-3.74 (m, 6H),3.63-3.56 (m, 4H), 3.10-3.05 (m, 2H), 2.85-2.80 (m, 2H), 1.70-1.59 (m,6H), 1.43 (s, 9H).

Example 201:7-[5-Amino-3-(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared fromN-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-7-[5-nitro-3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 290). MS (ESI): mass calcd. for C₂₇H₃₃F₃N₆, 498.27; m/z found,499.5 [M+H]⁺. ¹H NMR (CDCl₃): 7.99-7.95 (m, 1H), 7.63-7.56 (m, 2H),7.38-7.32 (m, 2H), 7.26-7.24 (m, 1H), 6.48 (s, 1H), 3.75-3.68 (m, 2H),3.25-3.18 (m, 4H), 3.19-3.12 (m, 2H), 3.08-2.97 (m, 1H), 2.91-2.84 (m,2H), 1.61-1.48 (m, 9H), 1.35-1.30 (m, 6H).

The following Examples 202-206 were prepared using methods analogous tothose described in Example 52, substituting the appropriate amidines inStep A and amines in Step C.

Example 202:N-[4-(1,1-Dimethylethyl)phenyl]-2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₈F₃N₅S, 487.20; m/z found, 488.1 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.88-7.86 (m, 1H), 7.51-7.47 (m, 2H),7.36-7.34 (m, 2H), 6.97-6.93 (m, 1H), 6.48 (s, 1H), 3.65-3.62 (m, 2H),3.60-3.57 (m, 2H), 3.18-3.14 (m, 2H), 2.94-2.90 (m, 2H), 2.52 (s, 3H),1.33 (s, 9H).

Example 203:N-[2-Chloro-4-(trifluoromethyl)phenyl]-2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₂H₁₈ClF₆N₅S, 533.09; m/z found, 534.1[M+H]⁺. ¹H NMR (DMSO): 9.48 (s, 1H), 9.16-9.14 (m, 1H), 8.74-8.71 (m,1H), 8.60 (d, J=2.0 Hz, 1H), 8.48 (d, J=8.5 Hz, 1H), 8.41-8.39 (m, 1H),7.81-7.78 (m, 1H), 4.20-4.17 (m, 4H), 3.78-3.72 (m, 4H), 2.91 (s, 3H).

Example 204:2-(Methylsulfanyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₃H₂₁F₆N₅S, 513.14; m/z found, 514 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.88(dd, J=7.8, 1.8 Hz, 1H), 7.49-7.44 (m, 2H), 6.99-6.92 (m, 1H), 6.42 (bs,1H), 3.68-3.62 (m, 2H), 3.62-3.54 (m, 2H), 3.21-3.15 (m, 2H), 2.98-2.92(m, 2H), 2.45 (s, 3H), 2.36 (s, 3H).

Example 205:2-(Methylsulfanyl)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₇F₃N₆S, 500.20; m/z found, 501 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),6.97-6.91 (m, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.78 (d, J=2.0 Hz, 1H), 6.74(dd, J=7.9, 2.1 Hz, 1H), 6.41 (bs, 1H), 3.66-3.61 (m, 2H), 3.61-3.55 (m,2H), 3.23 (t, J=5.6 Hz, 2H), 3.19-3.11 (m, 2H), 2.93-2.83 (m, 2H), 2.89(s, 3H), 2.73 (t, J=6.4 Hz, 2H), 2.52 (s, 3H), 2.03-1.93 (m, 2H).

Example 206:2-(Methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆S, 528.23; m/z found, 529 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.12 (d, J=8.2 Hz, 1H), 6.93 (dd, J=7.4, 4.7 Hz, 1H), 6.84-6.78 (m, 2H),6.41 (bs, 1H), 3.66-3.61 (m, 2H), 3.61-3.55 (m, 2H), 3.27-3.21 (m, 2H),3.17-3.11 (m, 2H), 2.93-2.86 (m, 2H), 2.91 (s, 3H), 2.53 (s, 3H),1.78-1.72 (m, 2H), 1.28 (s, 6H).

Examples 207-211 synthesized in a manner similar to Example 53substituting the appropriate amines in Step C of Example 52.

Example 207:N-[4-(1,1-Dimethylethyl)phenyl]-2-(methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared starting withN-[4-(1,1-dimethylethyl)phenyl]-2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 202). MS (ESI): mass calcd. for C₂₅H₂₈F₃N₅O₂S, 519.19; m/zfound, 520.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.88 (dd, J=7.8,1.8 Hz, 1H), 7.49-7.45 (m, 2H), 7.41-7.38 (m, 2H), 7.00-6.96 (m, 1H),6.77 (s, 1H), 3.72-3.67 (m, 2H), 3.64-3.59 (m, 2H), 3.36-3.31 (m, 2H),3.25 (s, 3H), 3.07-3.02 (m, 2H), 1.33 (s, 9H).

Example 208:2-(Methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared starting with2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 206). MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆O₂S, 560.22; m/zfound, 561 [M+H]⁺. ¹H NMR (CDCl₃): 8.57 (d, J=2.2 Hz, 0.6H), 8.51 (d,J=2.0 Hz, 0.4H), 8.43-8.37 (m, 1H), 8.07-7.94 (m, 1H), 7.91-7.85 (m,1H), 7.30-7.20 (m, 1H), 7.02-6.95 (m, 1H), 5.75-5.40 (m, 1H), 3.93-3.78(m, 2H), 3.68-3.47 (m, 7H), 3.44-3.21 (m, 4H), 2.90 (s, 1.5H), 2.87 (s,1.5H), 2.05-1.90 (m, 2H), 1.39 (s, 3H), 1.37 (s, 1.5H), 1.35 (s, 1.5H).

Example 209:2-(Methylsulfonyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared starting with2-(methylsulfanyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 204). MS (ESI): mass calcd. for C₂₃H₂₁F₆N₅O₂S, 545.13; m/zfound, 546 [M+H]⁺. ¹H NMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 7.96(d, J=8.2 Hz, 1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.55-7.48 (m, 2H), 7.00(dd, J=7.4, 4.7 Hz, 1H), 6.71 (bs, 1H), 3.74-3.67 (m, 2H), 3.66-3.59 (m,2H), 3.38-3.32 (m, 2H), 3.20 (s, 3H), 3.11-3.05 (m, 2H), 2.37 (s, 3H).

Example 210:2-(1-Methylethyl)-N-[4-(methylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared starting with2-(1-methylethyl)-N-[4-(methylsulfanyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 135). MS (ESI): mass calcd. for C₂₄H₂₆F₃N₅O₂S, 505.18; m/zfound, 506.4 [M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.92-7.86 (m,5H), 6.99-6.94 (m, 1H), 6.77 (s, 1H), 3.69-3.57 (m, 4H), 3.28-3.21 (m,2H), 3.11-3.04 (m, 4H), 3.02-2.99 (m, 2H), 1.33 (d, J=6.9 Hz, 6H).

Example 211: Methyl5-chloro-6-[2-(methylsulfonyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylate

The title compound was prepared starting from methyl5-chloro-6-[2-(methylsulfanyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylate(Example 303). MS (ESI): mass calcd. for C₂₃H₂₁ClF₃N₅O₄S, 555.10; m/zfound, 556.1 [M+H]⁺. ¹H NMR (CD₃OD): 8.50 (d, J=2.00 Hz, 1H), 7.96 (d,J=2.00 Hz, 1H), 7.54 (d, J=8.55 Hz, 2H), 7.44 (d, J=8.64 Hz, 2H), 6.93(s, 1H), 3.86-3.71 (m, 4H), 3.70 (s, 3H), 3.26-3.11 (m, 2H), 3.02-2.95(m, 2H).

The following Examples 212-277 were prepared using methods analogous tothose described in Example 55, substituting the appropriate amines.

Example 212:2-(1,1-Dioxido-1,2-thiazinan-2-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₂₄F₆N₆O₂S, 586.16; m/z found, 587.5[M+H]⁺. ¹H NMR (CDCl₃): 9.89-9.69 (m, 1H), 8.49-8.34 (m, 1H), 7.92 (d,J=7.0 Hz, 1H), 7.68-7.54 (m, 4H), 7.05 (dd, J=7.6, 4.7 Hz, 1H),4.15-4.08 (m, 2H), 3.68-3.52 (m, 4H), 3.43-3.34 (m, 2H), 3.28-3.08 (m,4H), 2.39-2.23 (m, 2H), 1.82-1.65 (m, 2H).

Example 213:N²-[2-(Methyloxy)ethyl]-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₄F₆N₆O, 526.19; m/z found, 527.5 [M+H]⁺.¹H NMR (CD₃OD): 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz,1H), 7.79 (d, J=8.5 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.14 (dd, J=7.7,4.8 Hz, 1H), 3.65-3.59 (m, 2H), 3.58-3.47 (m, 6H), 3.33-3.31 (m, 3H),3.20-3.15 (m, 2H), 3.11-3.07 (m, 2H).

Example 214:2-[3-(Methyloxy)piperidin-1-yl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆O, 566.22; m/z found, 567.6 [M+H]⁺.¹H NMR (CD₃OD): 8.47-8.43 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H), 7.71(s, 4H), 7.17-7.10 (m, 1H), 3.91-3.67 (m, 3H), 3.65-3.50 (m, 5H),3.43-3.36 (m, 1H), 3.29-3.26 (m, 2H), 3.20 (s, 3H), 3.12-3.07 (m, 2H),1.95-1.73 (m, 3H), 1.61-1.50 (m, 1H).

Example 215:2-{(2S)-2-[(Methyloxy)methyl]pyrrolidin-1-yl}-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆O, 566.22; m/z found, 567.6 [M+H]⁺.¹H NMR (CD₃OD): 8.46-8.43 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H), 7.80(d, J=8.5 Hz, 2H), 7.69 (d, J=8.6 Hz, 2H), 7.14 (dd, J=7.8, 4.8 Hz, 1H),4.34-4.25 (m, 1H), 3.66-3.37 (m, 9H), 3.29-3.20 (m, 4H), 3.14-3.07 (m,2H), 2.23-1.90 (m, 4H).

Example 216:N²-(Furan-2-ylmethyl)-N²-methyl-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₄F₆N₆O, 562.19; m/z found, 563.5 [M+H]⁺.¹H NMR (CD₃OD): 8.46-8.43 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H), 7.74(d, J=8.6 Hz, 2H), 7.66 (d, J=8.7 Hz, 2H), 7.50-7.46 (m, 1H), 7.14 (dd,J=7.8, 4.8 Hz, 1H), 6.37 (dd, J=3.2, 1.9 Hz, 1H), 6.17 (d, J=2.5 Hz,1H), 4.76 (s, 2H), 3.65-3.58 (m, 2H), 3.58-3.53 (m, 2H), 3.34-3.30 (m,2H), 3.21 (s, 3H), 3.14-3.09 (m, 2H).

Example 217:2-Azetidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₃H₂₁F₆N₇, 509.18; m/z found, 510.1 [M+H]⁺.¹H NMR (DMSO): 9.07 (d, J=2.4 Hz, 1H), 8.89 (s, 1H), 8.45 (dd, J=4.7,1.5 Hz, 1H), 8.43 (dd, J=8.7, 2.4 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz, 1H),7.77 (d, J=8.7 Hz, 1H), 7.10 (dd, J=7.6, 4.7 Hz, 1H), 3.97 (t, J=7.4 Hz,4H), 3.45-3.38 (m, 4H), 3.00-2.96 (m, 4H), 2.27-2.22 (m, 2H).

Example 218:N²,N²-Dimethyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₃H₂₃F₆N₇, 511.19; m/z found, 512.4 [M+H]⁺.¹H NMR (MeOD): 8.69 (d, J=1.6 Hz, 1H), 8.40 (dd, J=4.8, 1.5 Hz, 1H),8.02-7.96 (m, 2H), 7.77 (d, J=8.0 Hz, 1H), 7.10 (dd, J=7.5, 4.7 Hz, 1H),4.80 (s, 2H), 3.60-3.55 (m, 2H), 3.54-3.49 (m, 2H), 3.24-3.20 (m, 2H),3.13 (s, 6H), 2.96-2.93 (m, 2H).

Example 219:N²-[2-(Dimethylamino)ethyl]-N²-methyl-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₉F₆N₇, 553.24; m/z found, 554.2 [M+H]⁺.¹H NMR (MeOD): 8.48-8.45 (m, 1H), 8.04 (dd, J=7.9, 1.7 Hz, 1H), 7.78 (d,J=8.6 Hz, 2H), 7.67 (d, J=8.4 Hz, 2H), 7.19-7.12 (m, 1H), 3.93 (t, J=6.1Hz, 2H), 3.63-3.59 (m, 2H), 3.58-3.53 (m, 2H), 3.36-3.31 (m, 2H),3.29-3.24 (m, 2H), 3.23 (s, 3H), 3.12-3.08 (m, 2H), 2.57 (s, 6H).

Example 220:2-(4-Methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₆F₆N₈, 552.22; m/z found, 553.5 [M+H]⁺.¹H NMR (CDCl₃): 8.86 (d, J=2.4 Hz, 1H), 8.40-8.37 (m, 1H), 8.14 (dd,J=8.4, 2.3 Hz, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H), 7.65 (d, J=8.6 Hz,1H), 6.98-6.93 (m, 1H), 6.55 (s, 1H), 3.82-3.75 (m, 4H), 3.63-3.53 (m,4H), 3.14-3.05 (m, 2H), 2.95-2.87 (m, 2H), 2.50-2.43 (m, 4H), 2.34 (s,3H).

Example 221:N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(4-methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₆ClF₆N₇, 585.18; m/z found, 586.5 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.6, 1.5 Hz, 1H), 8.01 (d, J=1.9 Hz, 1H),7.87 (dd, J=7.8, 1.8 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.37-7.31 (m, 1H),6.95 (dd, J=7.5, 4.9 Hz, 1H), 6.53 (s, 1H), 3.84-3.77 (m, 4H), 3.62-3.52(m, 4H), 3.13-3.03 (m, 2H), 2.90-2.83 (m, 2H), 2.51-2.46 (m, 4H), 2.35(s, 3H).

Example 222:2-Azepan-1-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆, 550.23; m/z found, 551.5 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.36 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.72(d, J=8.5 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H), 6.93 (dd, J=7.5, 4.9 Hz, 1H),6.50 (s, 1H), 3.78-3.67 (m, 4H), 3.63-3.53 (m, 4H), 3.12-3.01 (m, 2H),2.89-2.83 (m, 2H), 1.83-1.74 (m, 4H), 1.65-1.47 (m, 4H).

Example 223:2-Azepan-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₇F₆N₇, 551.22; m/z found, 552.5 [M+H]⁺.¹H NMR (CDCl₃): 8.78 (d, J=2.5 Hz, 1H), 8.40-8.34 (m, 2H), 7.87 (dd,J=7.8, 1.8 Hz, 1H), 7.62 (d, J=8.7 Hz, 1H), 6.97-6.91 (m, 1H), 6.54 (s,1H), 3.76-3.68 (m, 4H), 3.63-3.52 (m, 4H), 3.13-3.05 (m, 2H), 2.93-2.87(m, 1H), 1.83-1.72 (m, 4H), 1.60-1.49 [(m, 4H) coincidental with waterpeak].

Example 224:2-Azepan-1-yl-N-[3-chloro-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇ClF₆N₆, 584.19; m/z found, 585.5 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.36 (m, 1H), 8.25 (d, J=1.9 Hz, 1H), 7.86 (dd,J=7.8, 1.8 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.32-7.28 (m, 1H), 6.96-6.91(m, 1H), 6.52 (s, 1H), 3.80-3.68 (m, 4H), 3.62-3.52 (m, 4H), 3.12-3.03(m, 2H), 2.89-2.83 (m, 2H), 1.86-1.76 (m, 4H), 1.61-1.50 [(m, 4H)coincidental with water peak].

Example 225:N²-[2-(Dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₅H₂₈F₆N₈, 554.23; m/z found, 555.5 [M+H]⁺.¹H NMR (CDCl₃): 8.77 (s, 1H), 8.40-8.37 (m, 1H), 8.36-8.32 (m, 1H), 7.87(dd, J=7.8, 1.8 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 6.98-6.92 (m, 1H), 6.54(s, 1H), 3.78-3.67 (m, 2H), 3.63-3.52 (m, 4H), 3.15 (s, 3H), 3.12-3.06(m, 2H), 2.94-2.87 (m, 2H), 2.54-2.46 (m, 2H), 2.28 (s, 6H).

Example 226:N⁴-[3-Chloro-4-(trifluoromethyl)phenyl]-N²-[2-(dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₆H₂₈ClF₆N₇, 587.20; m/z found, 588.5 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 8.02 (s, 1H), 7.87 (dd,J=7.8, 1.8 Hz, 1H), 7.57 (d, J=8.7 Hz, 1H), 7.43 (d, J=8.6 Hz, 1H), 6.94(dd, J=7.4, 4.9 Hz, 1H), 6.53 (s, 1H), 3.78-3.69 (m, 2H), 3.61-3.49 (m,4H), 3.17 (s, 3H), 3.11-3.05 (m, 2H), 2.89-2.82 (m, 2H), 2.54-2.48 (m,2H), 2.28 (s, 6H).

Example 227:N⁴-[(3,4-Dichlorophenyl)methyl]-N²-[2-(dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₃₀Cl₂F₃N₇, 567.19; m/z found, 568.5[M+H]⁺. ¹H NMR (MeOD): 8.42 (dd, J=4.7, 1.4 Hz, 1H), 8.01 (dd, J=7.8,1.8 Hz, 1H), 7.51 (d, J=8.3 Hz, 1H), 7.47-7.44 (m, 1H), 7.22 (dd, J=8.3,2.1 Hz, 1H), 7.14-7.08 (m, 1H), 4.73 (s, 2H), 4.00-3.93 (m, 2H),3.62-3.58 (m, 2H), 3.57-3.52 (m, 2H), 3.29-3.22 (m, 2H), 3.21 (s, 3H),3.01-2.96 (m, 2H), 2.78 (s, 6H).

Example 228:N²-Methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₅F₆N₇O, 541.20; m/z found, 542.5 [M+H]⁺.¹H NMR (MeOD): 8.47-8.44 (m, 1H), 8.26 (dd, J=8.5, 2.2 Hz, 1H), 8.03(dd, J=7.8, 1.7 Hz, 1H), 7.86 (d, J=8.6 Hz, 1H), 7.18-7.12 (m, 1H), 3.79(t, J=5.1 Hz, 2H), 3.65-3.53 (m, 6H), 3.32 (s, 3H), 3.32-3.29 (m, 2H),3.23 (s, 3H), 3.15-3.11 (m, 2H).

Example 229:N⁴-[3-Chloro-4-(trifluoromethyl)phenyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₂₅ClF₆N₆O, 574.17; m/z found, 575.5[M+H]⁺. ¹H NMR (MeOD): 8.45 (dd, J=4.7, 1.3 Hz, 1H), 8.05 (d, J=1.8 Hz,1H), 8.03 (dd, J=7.9, 1.7 Hz, 1H), 7.80-7.76 (m, 1H), 7.64 (d, J=8.7 Hz,1H), 7.18-7.11 (m, 1H), 3.86-3.79 (m, 2H), 3.65-3.58 (m, 4H), 3.56-3.51(m, 2H), 3.34 (s, 3H), 3.33-3.30 (m, 2H), 3.25 (s, 3H), 3.12-3.07 (m,2H).

Example 230:N⁴-[(3,4-Dichlorophenyl)methyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₂₇Cl₂F₃N₆O, 554.16; m/z found, 554.2[M+H]⁺. ¹H NMR (MeOD): 8.42-8.39 (m, 1H), 8.00 (dd, J=7.8, 1.7 Hz, 1H),7.46 (d, J=8.3 Hz, 1H), 7.44-7.42 (m, 1H), 7.21 (dd, J=8.3, 2.0 Hz, 1H),7.12-7.07 (m, 1H), 4.62 (s, 2H), 3.70 (t, J=5.1 Hz, 2H), 3.61-3.57 (m,2H), 3.56-3.50 (m, 2H), 3.38-3.32 (m, 2H), 3.25 (s, 3H), 3.24-3.19 (m,2H), 3.15 (s, 3H), 2.98-2.93 (m, 2H).

Example 231:2-Azetidin-1-yl-N-[3-chloro-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₁ClF₆N₆, 542.14; m/z found, 543.5 [M+H]⁺.¹H NMR (MeOD): 8.46-8.43 (m, 1H), 8.16-8.13 (m, 1H), 8.02 (dd, J=7.8,1.8 Hz, 1H), 7.76-7.73 (m, 2H), 7.16-7.11 (m, 1H), 4.30 (t, J=7.7 Hz,4H), 3.62-3.58 (m, 2H), 3.55-3.49 (m, 2H), 3.27-3.21 (m, 2H), 3.12-3.07(m, 2H), 2.55-2.45 (m, 2H).

Example 232:2-Azetidin-1-yl-N-[(3,4-dichlorophenyl)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₃Cl₂F₃N₆, 522.13; m/z found, 523.5[M+H]⁺. ¹H NMR (MeOD): 8.43-8.35 (m, 1H), 7.98 (dd, J=7.8, 1.7 Hz, 1H),7.50-7.42 (m, 2H), 7.27-7.20 (m, 1H), 7.11-7.05 (m, 1H), 4.62-4.55 (m,2H), 4.23-4.13 (m, 4H), 3.61-3.53 (m, 2H), 3.51-3.46 (m, 2H), 3.16-3.09(m, 2H), 2.94-2.86 (m, 2H), 2.49-2.37 (m, 2H).

Example 233:N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₅ClF₆N₆, 570.17; m/z found, 571.5 [M+H]⁺.¹H NMR (MeOD): 8.47-8.44 (m, 1H), 8.06-7.98 (m, 2H), 7.79 (d, J=8.7 Hz,1H), 7.62 (dd, J=8.6, 1.3 Hz, 1H), 7.18-7.12 (m, 1H), 3.79-3.71 (m, 4H),3.63-3.56 (m, 2H), 3.56-3.51 (m, 2H), 3.32-3.25 (m, 2H), 3.12-3.07 (m,2H), 1.81-1.66 (m, 6H).

Example 234:2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₇, 537.21; m/z found, 538.5 [M+H]⁺.¹H NMR (MeOD): 8.94 (d, J=2.4 Hz, 1H), 8.46 (dd, J=4.7, 1.3 Hz, 1H),8.20 (dd, J=8.3, 2.2 Hz, 1H), 8.04 (dd, J=7.9, 1.7 Hz, 1H), 7.87 (d,J=8.6 Hz, 1H), 7.18-7.13 (m, 1H), 3.74-3.68 (m, 4H), 3.64-3.58 (m, 2H),3.58-3.52 (m, 2H), 3.32-3.27 (m, 2H), 3.14-3.09 (m, 2H), 1.78-1.62 (m,6H).

Example 235:2-(2,6-Dimethylmorpholin-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆O, 566.22; m/z found, 566.2 [M+H]⁺.¹H NMR (MeOD): 8.45 (d, J=4.7 Hz, 1H), 8.03 (dd, J=7.8, 1.6 Hz, 1H),7.74-7.67 (m, 4H), 7.18-7.12 (m, 1H), 4.19 (d, J=13.1 Hz, 2H), 3.69-3.58(m, 4H), 3.58-3.52 (m, 2H), 3.30-3.25 (m, 2H), 3.14-3.08 (m, 2H),2.80-2.69 (m, 2H), 1.19 (d, J=6.2 Hz, 6H).

Example 236:2-[(2R,6S)-2,6-Dimethylmorpholin-4-yl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆O, 566.22; m/z found, 567.5 [M+H]⁺.¹H NMR (MeOD): 8.47-8.44 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H),7.74-7.68 (m, 4H), 7.17-7.12 (m, 1H), 4.20 (d, J=13.0 Hz, 2H), 3.71-3.58(m, 4H), 3.58-3.52 (m, 2H), 3.30-3.26 (m, 2H), 3.14-3.08 (m, 2H),2.80-2.68 (m, 2H), 1.19 (d, J=6.2 Hz, 6H).

Example 237:2-(1,4-Oxazepan-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆O, 552.20; m/z found, 553.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H), 7.66(d, J=8.4 Hz, 2H), 7.54 (d, J=8.6 Hz, 1H), 6.97-6.89 (m, 1H), 6.52 (s,1H), 3.94-3.85 (m, 4H), 3.84-3.78 (m, 2H), 3.74-3.70 (m, 2H), 3.63-3.54(m, 4H), 3.11-3.04 (m, 2H), 2.91-2.85 (m, 2H), 2.04-1.95 (m, 2H).

Example 238:2-(3,3-Difluoropiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₄F₅N₆, 572.19; m/z found, 573.1 [M+H]⁺.¹H NMR (MeOD): 8.46-8.43 (m, 1H), 8.02 (dd, J=7.8, 1.7 Hz, 1H),7.73-7.67 (m, 4H), 7.16-7.11 (m, 1H), 4.02 (t, J=11.4 Hz, 2H), 3.79-3.74(m, 2H), 3.64-3.59 (m, 2H), 3.57-3.53 (m, 2H), 3.30-3.27 (m, 2H),3.13-3.08 (m, 2H), 2.21-2.09 (m, 2H), 1.91-1.80 (m, 2H).

Example 239:2-(4-Methylpiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆, 550.2; m/z found, 551.5 [M+H]⁺. ¹HNMR (MeOD): 8.47-8.43 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H), 7.75-7.67(m, 4H), 7.18-7.10 (m, 1H), 4.34 (d, J=13.5 Hz, 2H), 3.66-3.57 (m, 2H),3.57-3.51 (m, 2H), 3.30-3.24 (m, 2H), 3.15-3.02 (m, 4H), 1.85-1.67 (m,3H), 1.29-1.09 (m, 2H), 0.99 (d, J=6.3 Hz, 3H).

Example 240:2-(3-Methylpiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆, 550.2; m/z found, 551.6 [M+H]⁺. ¹HNMR (MeOD): 8.47-8.43 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H), 7.75-7.67(m, 4H), 7.19-7.10 (m, 1H), 4.32-4.15 (m, 2H), 3.63-3.57 (m, 2H),3.57-3.51 (m, 2H), 3.30-3.24 (m, 2H), 3.13-3.01 (m, 3H), 2.82-2.66 (m,1H), 1.93-1.73 (m, 2H), 1.73-1.45 (m, 2H), 1.34-1.17 (m, 1H), 0.94 (d,J=6.6 Hz, 3H).

Example 241:2-(3,3-Difluoroazetidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₀F₈N₆, 544.16; m/z found, 545.5 [M+H]⁺.¹H NMR (MeOD): 8.45 (dd, J=4.8, 1.4 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz,1H), 7.80 (d, J=8.5 Hz, 2H), 7.71 (d, J=8.6 Hz, 2H), 7.18-7.11 (m, 1H),4.64-4.59 (m, 4H), 3.65-3.59 (m, 2H), 3.58-3.53 (m, 2H), 3.29-3.23 (m,2H), 3.16-3.10 (m, 2H).

Example 242:2-(4,4-Difluoropiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₄F₅N₆, 572.19; m/z found, 573.1 [M+H]⁺.¹H NMR (CDCl₃): 8.39 (dd, J=4.7, 1.6 Hz, 1H), 7.87 (dd, J=7.8, 1.8 Hz,1H), 7.63-7.55 (m, 4H), 6.98-6.91 (m, 1H), 6.53 (s, 1H), 3.95-3.88 (m,4H), 3.62-3.58 (m, 2H), 3.58-3.54 (m, 2H), 3.11-3.06 (m, 2H), 2.91-2.86(m, 2H), 2.04-1.93 (m, 4H).

Example 243:2-(3,3-Difluoropyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₂₂F₈N₆, 558.18 m/z found, 559.5 [M+H]⁺. ¹HNMR (MeOD): 8.45 (dd, J=4.4, 1.4 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz, 1H),7.81 (d, J=8.6 Hz, 2H), 7.71 (d, J=8.661 Hz, 2H), 7.16-7.11 (m, 1H),3.99-3.92 (m, 2H), 3.84 (t, J=7.4 Hz, 2H), 3.64-3.58 (m, 2H), 3.57-3.52(m, 2H), 3.31-3.27 (m, 2H), 3.15-3.10 (m, 2H), 2.62-2.50 (m, 2H).

Example 244:2-(2-Methylpyrrolidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆, 536.21; m/z found, 537.6 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.7, 1.6 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz,1H), 7.77 (d, J=8.6 Hz, 2H), 7.55 (d, J=8.6 Hz, 2H), 6.95-6.91 (m, 1H),6.52 (s, 1H), 4.33-4.24 (m, 1H), 3.68-3.49 (m, 6H), 3.13-3.05 (m, 2H),2.90-2.85 (m, 2H), 2.13-2.00 (m, 2H), 1.97-1.88 (m, 1H), 1.74-1.65 (m,1H), 1.26 (d, J=6.3 Hz, 3H).

Example 245:N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(1,4-oxazepan-4-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₆H₂₅ClF₆N₆O, 586.17; m/z found, 587.5[M+H]⁺. ¹H NMR (MeOD): 8.46-8.44 (m, 1H), 8.04-8.00 (m, 2H), 7.79 (d,J=8.7 Hz, 1H), 7.64-7.59 (m, 1H), 7.17-7.11 (m, 1H), 3.92-3.81 (m, 6H),3.80-3.76 (m, 2H), 3.64-3.59 (m, 2H), 3.57-3.52 (m, 2H), 3.36-3.32 (m,2H), 3.13-3.09 (m, 2H).

Example 246:2-(2-Methylpiperidin-1-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminehydrochloride salt

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆, 550.23; m/z found, 551.6 [M+H]⁺.¹H NMR (MeOD): 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.03 (dd, J=7.8, 1.8 Hz,1H), 7.74-7.68 (m, 4H), 7.17-7.11 (m, 1H), 4.70-4.63 (m, 1H), 4.19-4.11(m, 1H), 3.64-3.58 (m, 2H), 3.56-3.52 (m, 2H), 3.30-3.26 (m, 2H),3.24-3.15 (m, 1H), 3.12-3.07 (m, 2H), 1.85-1.62 (m, 5H), 1.58-1.46 (m,1H), 1.27 (d, J=6.9 Hz, 3H).

Example 247:2-(1,1-Dioxidothiomorpholin-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₂₄F₆N₆O₂S, 586.16; m/z found, 587.1[M+H]⁺. ¹H NMR ((CD₃)₂CO): 8.46-8.44 (m, 1H), 8.02-8.00 (m, 1H),7.88-7.84 (m, 2H), 7.64-7.62 (m, 2H), 7.13-7.08 (m, 1H), 4.31-4.25 (m,4H), 3.56-3.48 (m, 4H), 3.14-3.04 (m, 6H), 2.07-2.04 (m, 2H).

Example 248:N-[4-(1,1-Dimethylethyl)phenyl]-2-pyrrolidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₃₃F₃N₆, 510.27; m/z found, 511.2 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.36 (m, 1H), 7.85 (dd, J=7.8, 1.8 Hz, 1H),7.62-7.58 (m, 2H), 7.34-7.31 (m, 2H), 6.94-6.90 (m, 1H), 6.35 (s, 1H),3.61-3.56 (m, 8H), 3.09-3.06 (m, 2H), 2.86-2.82 (m, 2H), 1.99-1.92 (m,4H), 1.32 (s, 9H).

Example 249:2-Azetidin-1-yl-N-[4-(1,1-dimethylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆, 496.26; m/z found, 497.2 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.37 (m, 1H), 7.85 (dd, J=7.7, 1.9 Hz, 1H),7.58-7.54 (m, 2H), 7.33-7.30 (m, 2H), 6.94-6.90 (m, 1H), 6.37 (s, 1H),4.15-4.10 (m, 4H), 3.62-3.54 (m, 4H), 3.10-3.05 (m, 2H), 2.86-2.81 (m,2H), 2.35-2.28 (m, 2H), 1.31 (s, 9H).

Example 250:2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₇, 537.21; m/z found, 538.2 [M+H]⁺.¹H NMR (CDCl₃): 8.49-8.47 (m, 1H), 8.43 (d, J=8.9 Hz, 1H), 8.40-8.39 (m,1H), 7.89-7.85 (m, 2H), 7.42 (s, 1H), 6.97-6.92 (m, 1H), 3.79-3.74 (m,4H), 3.58-3.52 (m, 4H), 3.12-3.06 (m, 2H), 2.95-2.88 (m, 2H), 1.73-1.59(m, 6H).

Example 251:N-[(3,4-Dichlorophenyl)methyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₇Cl₂F₃N₆, 551.16; m/z found, 551.1[M+H]⁺. ¹H NMR (CDCl₃): 8.36-8.35 (m, 1H), 7.84 (dd, J=7.8, 1.8 Hz, 1H),7.44-7.43 (m, 1H), 7.37 (d, J=8.2 Hz, 1H), 7.18-7.16 (m, 1H), 6.92-6.89(m, 1H), 4.82-4.79 (m, 1H), 4.59 (d, J=5.7 Hz, 2H), 3.69-3.65 (m, 4H),3.57-3.52 (m, 4H), 3.03-2.99 (m, 2H), 2.72-2.69 (m, 2H), 1.64-1.59 (m,2H), 1.56-1.50 (m, 4H).

Example 252:N-[4-(1,1-Dimethylethyl)phenyl]-2-(4-methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₆F₃N₇, 539.30; m/z found, 540.2 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.7 Hz, 1H),7.48-7.45 (m, 2H), 7.36-7.32 (m, 2H), 6.94-6.90 (m, 1H), 6.34 (s, 1H),3.84-3.76 (m, 4H), 3.64-3.55 (m, 4H), 3.09-3.04 (m, 2H), 2.87-2.81 (m,2H), 2.51-2.42 (m, 4H), 2.34 (s, 3H), 1.33 (s, 9H).

Example 253:2-Azepan-1-yl-N-[4-(1,1-dimethylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₀H₃₇F₃N₆, 538.30; m/z found, 539.2 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.85 (dd, J=7.8, 1.7 Hz, 1H),7.56-7.53 (m, 2H), 7.33-7.30 (m, 2H), 6.93-6.90 (m, 1H), 6.31 (s, 1H),3.76-3.70 (m, 4H), 3.63-3.56 (m, 4H), 3.08-3.04 (m, 2H), 2.86-2.82 (m,2H), 1.83-1.74 (m, 4H), 1.58-1.52 (m, 4H), 1.32 (s, 9H).

Example 254:N²-[2-(Dimethylamino)ethyl]-N⁴-[4-(1,1-dimethylethyl)phenyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₉H₃₈F₃N₇, 541.31; m/z found, 542.3 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.37 (m, 1H), 7.86-7.85 (m, 1H), 7.50-7.46 (m, 2H),7.33-7.30 (m, 2H), 6.94-6.90 (m, 1H), 6.29 (s, 1H), 3.72-3.70, (m, 2H),3.63-3.55 (m, 4H), 3.15 (s, 3H), 3.08-3.04 (m, 2H), 2.86-2.82 (m, 2H),2.52-2.46 (m, 2H), 2.26 (s, 6H), 1.31 (s, 9H).

Example 255:2-Azepan-1-yl-N-[(3,4-dichlorophenyl)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₉Cl₂F₃N₆, 564.18; m/z found, 565.1[M+H]⁺. ¹H NMR (CDCl₃): 8.37-8.35 (m, 1H), 7.86-7.83 (m, 1H), 7.43-7.42(m, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.17-7.15 (m, 1H), 6.91-6.89 (m, 1H),4.83-4.79 (m, 1H), 4.59 (d, J=5.7 Hz, 2H), 3.69-3.52 (m, 8H), 3.03-3.00(m, 2H), 2.72-2.69 (m, 2H), 1.72-1.61 (m, 4H), 1.52-1.47 (m, 4H).

Example 256:N-[(3,4-Dichlorophenyl)methyl]-2-(4-methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₈Cl₂F₃N₇, 565.17; m/z found, 566.1[M+H]⁺. ¹H NMR (CDCl₃): 8.37-8.35 (m, 1H), 7.86-7.84 (m, 1H), 7.44-7.43(m, 1H), 7.38 (d, J=8.2 Hz, 1H), 7.17-7.15 (m, 1H), 6.93-6.90 (m, 1H),4.86-4.82 (m, 1H), 4.60 (d, J=5.7 Hz, 2H), 3.77-3.69 (m, 4H), 3.57-3.52(m, 4H), 3.04-3.00 (m, 2H), 2.73-2.69 (m, 2H), 2.43-2.39 (m, 4H), 2.32(s, 3H).

Example 257:N⁴-[4-(1,1-Dimethylethyl)phenyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₈H₃₅F₃N₆O, 528.28; m/z found, 529.2 [M+H]⁺.¹H NMR (CDCl₃): 8.38-8.37 (m, 1H), 7.86 (dd, J=7.8, 1.9 Hz, 1H),7.52-7.49 (m, 2H), 7.34-7.30 (m, 2H), 6.94-6.90 (m, 1H), 6.32 (s, 1H),3.77 (t, J=6.1 Hz, 2H), 3.62-3.56 (m, 6H), 3.34 (s, 3H), 3.19 (s, 3H),3.07-3.05 (m, 2H), 2.86-2.82 (m, 2H), 1.32 (s, 9H).

Example 258:N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-pyrrolidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₃ClF₆N₆, 556.16; m/z found, 557.4 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.38 (m, 1H), 8.23 (d, J=1.9 Hz, 1H), 7.87 (dd,J=7.8, 1.8 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.46-7.42 (m, 1H), 6.97-6.93(m, 1H), 6.54 (s, 1H), 3.65-3.53 (m, 8H), 3.14-3.06 (m, 2H), 2.90-2.84(m, 2H), 2.02-1.94 (m, 4H).

Example 259:[1-(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)piperidin-2-yl]methanol

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆O, 566.22; m/z found, 567.5 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.65-7.61 (m, 2H), 7.59-7.56 (m, 2H), 6.97-6.92 (m, 1H), 6.52 (s, 1H),4.94-4.87 (m, 1H), 4.58-4.51 (m, 1H), 4.05-4.00 (m, 1H), 3.74-3.65 (m,2H), 3.61-3.53 (m, 4H), 3.15-3.04 (m, 3H), 2.89-2.84 (m, 2H), 1.78-1.57(m, 5H).

Example 260:[(2S)-1-(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)pyrrolidin-2-yl]methanolhydrochloride salt

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆O, 552.21; m/z found, 553.1 [M+H]⁺.¹H NMR (CD₃OD): 8.48-8.45 (m, 1H), 8.06-8.01 (m, 1H), 7.86-7.81 (m, 2H),7.72-7.67 (m, 2H), 7.19-7.12 (m, 1H), 4.26-4.14 (m, 1H), 3.87-3.49 (m,8H), 3.30-3.19 (m, 2H), 3.15-3.08 (m, 2H), 2.23-1.85 (m, 4H).

Example 261:[(2R)-1-(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)pyrrolidin-2-yl]methanolhydrochloride salt

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆O, 552.21; m/z found, 553.1 [M+H]⁺.¹H NMR (CD₃OD): 8.47-8.44 (m, 1H), 8.04-8.01 (m, 1H), 7.84-7.81 (m, 2H),7.71-7.69 (m, 2H), 7.16-7.12 (m, 1H), 4.24-4.16 (m, 1H), 3.84-3.52 (m,8H), 3.28-3.20 (m, 2H), 3.13-3.10 (m, 2H), 2.22-1.85 (m, 4H).

Example 262:[(2S)-1-(7-[3-(Trifluoromethyl)pyridin-2-yl]-4-{[5-(trifluoromethyl)pyridin-2-yl]amino}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)pyrrolidin-2-yl]methanolhydrochloride salt

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₇O, 553.20; m/z found, 554.1 [M+H]⁺.¹H NMR (CDCl₃): 8.66-8.62 (m, 1H), 8.50-8.40 (m, 2H), 8.07-8.01 (m, 1H),7.94-7.89 (m, 1H), 7.07-7.02 (m, 1H), 5.15-5.03 (m, 1H), 3.91-3.56 (m,10H), 3.09-2.98 (m, 2H), 2.16-1.99 (m, 4H).

Example 263:N²-[(3R)-Tetrahydrofuran-3-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₇O, 539.19; m/z found, 540.2 [M+H]⁺.¹H NMR (CD₃OD): 8.56-8.54 (m, 1H), 8.46-8.43 (m, 2H), 8.04-7.99 (m, 2H),7.14-7.10 (m, 1H), 4.55-4.49 (m, 1H), 4.01-3.95 (m, 2H), 3.90-3.83 (m,1H), 3.73-3.69 (m, 1H), 3.51-3.44 (m, 4H), 3.10-3.01 (m, 4H), 2.36-2.26(m, 1H), 2.01-1.92 (m, 1H).

Example 264:N⁴-[4-(1,1-Dimethylethyl)phenyl]-N²-[(3R)-tetrahydrofuran-3-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₈H₃₃F₃N₆O, 526.27; m/z found, 527.3 [M+H]⁺.¹H NMR (CD₃OD): 8.33-8.32 (m, 1H), 7.90 (dd, J=7.8, 1.8 Hz, 1H),7.41-7.37 (m, 2H), 7.25-7.22 (m, 2H), 7.02-6.99 (m, 1H), 4.32-4.27 (m,1H), 3.85-3.76 (m, 2H), 3.73-3.68 (m, 1H), 3.52 (dd, J=9.0, 3.9 Hz, 1H),3.37-3.34 (m, 4H), 2.92-2.84 (m, 4H), 2.17-2.09 (m, 1H), 1.81-1.74 (m,1H), 1.22 (s, 9H).

Example 265:N²-(Tetrahydro-furan-3-yl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₅H₂₄F₆N₆O, 538.19; m/z found, 539.2 [M+H]⁺.¹H NMR (CD₃OD): 8.49-8.46 (m, 1H), 8.04 (dd, J=7.8, 1.7 Hz, 1H), 7.78(d, J=8.6 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 7.19-7.15 (m, 1H), 4.42-4.38(m, 1H), 3.98-3.92 (m, 1H), 3.84-3.78 (m, 2H), 3.71 (dd, J=9.5, 3.2 Hz,1H), 3.65-3.62 (m, 2H), 3.57-3.55 (m, 2H), 3.23-3.18 (m, 2H), 3.14-3.10(m, 2H), 2.31-2.22 (m, 1H), 1.98-1.92 (m, 1H).

Example 266:N²-Methyl-N²-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₄H₂₅F₆N₇, 525.21; m/z found, 526.2 [M+H]⁺.

Example 267:N²-Cyclohexyl-N²-methyl-N⁴-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₉H₃₂F₆N₆, 578.26; m/z found, 579.3 [M+H]⁺.

Example 268:2-(7-Azabicyclo[2.2.1]hept-7-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₆F₆N₆, 548.521 m/z found, 549.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.89-7.87 (m, 1H), 7.71 (d, J=8.5 Hz,2H), 7.59 (d, J=8.5 Hz, 2H), 6.97-6.94 (m, 1H), 6.55 (s, 1H), 4.63 (s,2H), 3.62-3.56 (m, 4H), 3.12-3.10 (m, 2H), 2.91-2.89 (m, 2H), 1.84-1.80(m, 4H), 1.51-1.46 (m, 4H).

Example 269:2-[2-(1-Methylethyl)pyrrolidin-1-yl]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₂F₆N₆, 578.26; m/z found, 579.3 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 2H), 7.88-7.85 (m, 1H), 7.45-7.42 (m, 2H),6.95-6.91 (m, 1H), 6.33 (s, 1H), 4.04-4.02 (m, 1H), 3.76-3.69 (m, 1H),3.65-3.56 (m, 4H), 3.54-3.48 (m, 1H), 3.11-3.08 (m, 2H), 2.89-2.86 (m,2H), 2.42-2.37 (m, 1H), 2.35 (s, 3H), 1.96-1.87 (m, 1H), 1.86-1.80 (m,3H), 0.86 (d, J=9.0 Hz, 3H), 0.77 (d, J=9.0 Hz, 3H).

Example 270:N²-(Cyclohexylmethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₇H₂₉F₆N₇, 565.24; m/z found, 566.3 [M+H]⁺.¹H NMR (CDCl₃): 8.75 (s, 1H), 8.40-8.38 (m, 2H), 7.88-7.86 (m, 1H), 7.62(d, J=8.5 Hz, 1H), 6.97-6.94 (m, 1H), 6.60 (s, 1H), 3.60-3.55 (m, 4H),3.22 (t, J=6.0 Hz, 2H), 3.08-3.05 (m, 2H), 2.91-2.89 (m, 2H), 1.80-1.72(m, 3H), 1.68-1.64 (m, 1H), 1.63-1.51 (m, 3H), 1.27-1.22 (m, 3H),1.02-0.94 (m, 2H).

Example 271:[4-(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)morpholin-2-yl]methanol

MS (ESI): mass calcd. for C₂₆H₂₆F₆N₆O₂, 568.20; m/z found, 569.3 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.38 (m, 1H), 7.88-7.86 (m, 1H), 7.62 (d, J=11.0Hz, 2H), 7.56 (d, J=11.0 Hz, 2H), 6.97-6.93 (m, 1H), 6.54 (s, 1H),4.48-4.38 (m, 2H), 4.04-4.01 (m, 1H), 3.76-3.72 (m, 1H), 3.70-3.62 (m,3H), 3.61-3.52 (m, 4H), 3.10-3.06 (m, 3H), 2.89-2.86 (m, 3H), 2.03-1.95(m, 1H).

Example 272:N²-Methyl-N²-(1-methylethyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₅H₂₆F₆N₆, 524.21; m/z found, 525.3 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.88-7.85 (m, 1H), 7.70 (d, J=8.5 Hz,2H), 7.55 (d, J=8.5 Hz, 2H), 6.95-6.92 (m, 1H), 6.50 (s, 1H), 5.05-5.00(m, 1H), 3.61-3.56 (m, 4H), 3.11-3.07 (m, 2H), 2.98 (s, 3H), 2.90-2.84(m, 2H), 1.18 (d, J=6.5 Hz, 6H).

Example 273:[4-(4-{[2-Methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)morpholin-2-yl]methanol

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆O₂, 582.22; m/z found, 583.3 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 8.04 (d, J=11.5 Hz, 1H), 7.88-7.86(m, 1H), 7.45 (d, J=9.0 Hz, 2H), 6.96-6.93 (m, 1H), 6.31 (s, 1H),4.43-4.34 (m, 2H), 4.02-3.98 (m, 1H), 3.74-3.71 (m, 1H), 3.66-3.55 (m,7H), 3.11-3.08 (m, 2H), 3.07-2.99 (m, 1H), 2.89-2.80 (m, 3H), 2.34 (s,3H), 1.99 (br s, 1H).

Example 274:2-[2-(1-Methylethyl)pyrrolidin-1-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₉F₆N₇, 565.24; m/z found, 566.3 [M+H]⁺.¹H NMR (CDCl₃): 8.86 (d, J=2.5 Hz, 1H), 8.41-8.40 (m, 1H), 8.14-8.11 (m,1H), 7.90-7.88 (m, 1H), 7.66 (d, J=9.0 Hz, 1H), 6.99-6.96 (m, 1H), 6.60(s, 1H), 4.47 (d, J=13.0 Hz, 1H), 4.39 (d, J=13.0 Hz, 1H), 4.06-4.03 (m,1H), 3.79-3.75 (m, 1H), 3.71-3.56 (m, 7H), 3.13-3.05 (m, 3H), 2.95-2.85(m, 3H), 2.07 (2.04 (m, 1H).

Example 275:N²-Cyclohexyl-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine

MS (ESI): mass calcd. for C₂₇H₂₉F₆N₇, 565.24; m/z found, 566.3 [M+H]⁺.¹H NMR (CDCl₃): 8.70 (s, 1H), 8.42 (d, J=10.0 Hz, 1H), 8.39-8.38 (m,1H), 7.88-7.86 (m, 1H), 7.61 (d, J=10.0 Hz, 1H), 7.00-6.93 (m, 1H), 6.55(s, 1H), 4.49 (br s, 1H), 3.61-3.55 (m, 4H), 3.11-3.08 (m, 2H), 3.01 (s,3H), 2.91-2.88 (m, 2H), 1.87-1.84 (m, 2H), 1.75-1.71 (m, 3H), 1.52-1.12(m, 5H).

Example 276:2-(2R)-2-Methylpiperidin-1-yl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆, 550.23; m/z found, 551.3 [M+H]⁺.¹H NMR (CD₃OD): 8.53-8.35 (m, 1H), 8.08-7.97 (m, 1H), 7.80 (d, J=8.8 Hz,2H), 7.55 (d, J=8.4 Hz, 2H), 7.18-7.07 (m, 1H), 3.59-2.87 (m, 12H),2.02-1.52 (m, 4H), 1.20 (d, J=6.8 Hz, 3H). [α]^(D) ₂₀=+58.2 (c=0.005,MeOH).

Example 277:2-[(2S)-2-Methylpiperidin-1-yl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆, 550.23; m/z found, 551.3 [M+H]⁺.¹H NMR (CD₃OD): 8.54-8.33 (m, 1H), 8.02 (dd, J=7.9, 1.8 Hz, 1H), 7.80(d, J=8.5 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H), 7.17-7.07 (m, 1H), 3.60-3.37(m, 2H), 3.36-3.31 (m, 2H), 3.11-2.97 (m, 4H), 1.80-1.68 (m, 4H),1.66-1.60 (m, 4H), 1.20 (d, J=6.89 Hz, 3H). [α]^(D) ₂₀=−53.8 (c=0.005,MeOH).

The following Examples 278-280 were prepared using methods analogous tothose described in Example 54, substituting the appropriate amines.

Example 278:N²-(2-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₈H₂₄F₆N₆, 558.19; m/z found, 559.4 [M+H]⁺.¹H NMR (MeOD): 8.45 (dd, J=4.7, 1.5 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz,1H), 7.58 (d, J=8.5 Hz, 2H), 7.41 (d, J=8.6 Hz, 2H), 7.33-7.28 (m, 3H),7.28-7.22 (m, 1H), 7.14 (dd, J=7.7, 4.8 Hz, 1H), 3.66-3.62 (m, 2H),3.57-3.54 (m, 2H), 3.27-3.23 (m, 2H), 3.14-3.09 (m, 2H), 2.21 (s, 3H).

Example 279:N²-(3-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₈H₂₄F₆N₆, 558.20; m/z found, 559.1 [M+H]⁺.¹H NMR (MeOD): 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.02 (dd, J=7.8, 1.8 Hz,1H), 7.67 (d, J=8.5 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.17-7.11 (m, 3H),7.01-6.96 (m, 1H), 3.67-3.59 (m, 2H), 3.59-3.55 (m, 2H), 3.35 (s, 1H),3.26-3.23 (m, 2H), 3.14-3.09 (m, 2H), 2.20 (s, 3H).

Example 280:N²-(4-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₈H₂₄F₆N₆, 558.20; m/z found, 559.5 [M+H]⁺.¹H NMR (MeOD): 8.46 (dd, J=4.7, 1.3 Hz, 1H), 8.03 (dd, J=7.8, 1.7 Hz,1H), 7.65 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 7.21 (d, J=8.4 Hz,2H), 7.18-7.12 (m, 1H), 7.10 (d, J=8.2 Hz, 2H), 3.66-3.60 (m, 2H),3.59-3.53 (m, 2H), 3.25-3.19 (m, 2H), 3.14-3.08 (m, 2H), 2.33 (s, 3H).

The following Examples 281-295 were prepared using methods analogous tothose described in Example 26, substituting the appropriate 2-chloropyridines in Step C and anilines in Step E:

Example 281:N-{2-[2-(1-Methylethyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridin-3-yl}methanesulfonamide

The title compound was prepared using methods analogous to thosedescribed by Richardson, T. I. et al. J. Med. Chem. 2004, 47, 744)starting from[7-(2-amino-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine(Example 84). MS (ESI): mass calcd. for C₂₄H₂₇F₃N₆O₂S, 520.20; m/zfound, 521.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.11 (dd, J=4.8, 1.6 Hz, 1H),7.82-7.76 (m, 3H), 7.61-7.58 (m, 2H), 7.09 (dd, J=8.1, 4.8 Hz, 1H),6.81-6.51 (m, 1H), 3.36-3.30 (m, 4H), 3.28-3.20 (m, 2H), 3.15-3.13 (m,3H), 3.11-3.03 (m, 1H), 3.03-2.96 (m, 2H), 1.34 (d, J=6.9 Hz, 6H).

Example 282:2-(1-Methylethyl)-7-[3-(methylsulfonyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared analogously to the methods described inExample 26, substituting 2-chloro-3-methanesulfonyl-pyridine (J. Org.Chem. 1979, 44(17), 3080-3082) in Step C. MS (ESI): mass calcd. forC₂₃H₂₅F₃N₆O₂S, 506.17; m/z found, 507.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.78(dd, J=4.8, 1.9 Hz, 1H), 8.48 (dd, J=7.9, 1.9 Hz, 1H), 8.09-8.07 (m,1H), 7.53 (dd, J=7.9, 4.8 Hz, 1H), 7.45 (d, J=8.6 Hz, 1H), 6.90 (dd,J=8.5, 2.7 Hz, 1H), 5.96-5.78 (m, 1H), 4.25-4.00 (m, 2H), 3.58-3.52 (m,2H), 3.24 (s, 3H), 3.20-3.13 (m, 2H), 2.95-2.91 (m, 2H), 2.91-2.81 (m,1H), 1.18 (d, J=6.9 Hz, 6H).

Example 283:7-[3-(Methylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared analogously to the methods described inExample 26, substituting 2-chloro-3-methanesulfonyl-pyridine (J. Org.Chem. 1979, 44(17), 3080-3082) in Step C. MS (ESI): mass calcd. forC₂₁H₂₀F₃N₅O₂S, 463.13; m/z found, 464 [M+H]⁺. ¹H NMR (CDCl₃): 8.66-8.60(m, 1H), 8.55 (dd, J=4.8, 1.9 Hz, 1H), 8.38 (dd, J=7.8, 1.9 Hz, 1H),7.73 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.6 Hz, 2H), 7.28-7.24 (m, 1H),3.67-3.59 (m, 2H), 3.59-3.54 (m, 2H), 3.39-3.28 (m, 2H), 3.14-3.05 (m,2H), 2.99 (s, 3H).

Example 284:7-(3-Aminopyridin-2-yl)-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₃₄N₆, 430.28; m/z found, 431.2 [M+H]⁺. ¹HNMR (CDCl₃): 7.78 (dd, J=4.8, 1.6 Hz, 1H), 7.63-7.56 (m, 2H), 7.39-7.32(m, 2H), 7.01-6.95 (m, 1H), 6.88-6.83 (m, 1H), 6.51-6.47 (m, 1H),3.87-3.75 (m, 2H), 3.44-3.30 (m, 4H), 3.23-3.15 (m, 2H), 3.08-2.99 (m,1H), 2.94-2.88 (m, 2H), 1.37-1.30 (m, 1H).

Example 285:7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₁ClF₃N₅, 517.22; m/z found, 518.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.26 (m, 1H), 7.64-7.55 (m, 2H), 7.40-7.33 (m, 2H),7.28-7.23 (m, 1H), 3.99-3.78 (m, 4H), 3.28-3.17 (m, 2H), 3.08-2.94 (m,3H), 1.43-1.26 (m, 6H).

Example 286:7-(5-Bromo-3-chloropyridin-2-yl)-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₃₁BrClN₅, 527.15; m/z found, 530.1 [M+H]⁺.¹H NMR (CDCl₃): 8.21-8.08 (m, 1H), 7.73-7.68 (m, 1H), 7.63-7.57 (m, 2H),7.40-7.31 (m, 2H), 6.46 (s, 1H), 3.79-3.58 (m, 4H), 3.26-3.15 (m, 2H),3.06-2.98 (m, 1H), 2.96-2.91 (m, 2H), 1.37-1.30 (m, 6H).

Example 287:7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(1-methylethyl)-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₂ClF₆N₅, 529.15; m/z found, 530.1 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.28 (m, 1H), 7.83-7.77 (m, 2H), 7.77-7.74 (m, 1H),7.62-7.57 (m, 2H), 3.99-3.81 (m, 4H), 3.33-3.18 (m, 2H), 3.11-2.98 (m,3H), 1.32 (d, J=6.9 Hz, 6H).

Example 288:5-Chloro-6-[2-(1-methylethyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylicacid trifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₃ClF₃N₅O₂, 505.15; m/z found, 506.1[M+H]⁺. ¹H NMR (CD₃OD): 8.75-8.57 (m, 1H), 8.18-8.10 (m, 1H), 7.87-7.78(m, 2H), 7.72-7.67 (m, 2H), 4.08-3.82 (m, 4H), 3.43-3.34 (m, 2H),3.28-3.22 (m, 2H), 3.10-3.02 (m, 1H), 1.29 (d, J=6.8 Hz, 6H).

Example 289:N-[4-(1,1-Dimethylethyl)phenyl]-2-(1-methylethyl)-7-(3-methyl-5-nitropyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₄N₆O₂, 474.27; m/z found, 475.5 [M+H]⁺.¹H NMR (CDCl₃): 8.97-8.85 (m, 1H), 8.16-8.02 (m, 1H), 7.63-7.54 (m, 2H),7.39-7.33 (m, 2H), 6.45 (s, 1H), 3.99-3.88 (m, 2H), 3.86-3.81 (m, 2H),3.27-3.16 (m, 2H), 3.05-2.94 (m, 3H), 2.39 (s, 3H), 1.34-1.33 (m, 9H),1.31 (d, J=6.9 Hz, 6H).

Example 290:N-[4-(1,1-Dimethylethyl)phenyl]-2-(1-methylethyl)-7-[5-nitro-3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆O₂, 528.25; m/z found, 529.5 [M+H]⁺.¹H NMR (CDCl₃): 9.12-9.01 (m, 1H), 8.63-8.57 (m, 1H), 7.67-7.50 (m, 2H),7.40-7.32 (m, 2H), 6.38 (s, 1H), 4.22-4.14 (m, 2H), 4.00-3.95 (m, 2H),3.32-3.22 (m, 2H), 3.06-3.02 (m, 2H), 3.02-2.95 (m, 1H), 1.34-1.32 (m,9H), 1.29 (d, J=6.9 Hz, 6H).

Example 291:2-(1-Methylethyl)-7-[5-nitro-3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₂F₆N₆O₂, 540.17; m/z found, 541.5 [M+H]⁺.¹H NMR (CDCl₃): 9.14-9.04 (m, 1H), 8.64-8.56 (m, 1H), 7.86-7.74 (m, 2H),7.63-7.58 (m, 2H), 6.57 (s, 1H), 4.23-4.15 (m, 2H), 4.02-3.94 (m, 2H),3.35-3.24 (m, 2H), 3.12-3.06 (m, 2H), 3.07-2.97 (m, 1H), 1.30 (d, J=6.9Hz, 6H).

Example 292:N-[4-(1,1-Dimethylethyl)phenyl]-7-(5-fluoro-3-methylpyridin-2-yl)-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared fromN-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-7-(3-methyl-5-nitropyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine(Example 289) using procedures analogous to those reported in US2000/006150343 and Marsais, F. et al. J. Heterocycl. Chem. 1988, 25(1),81. MS (ESI): mass calcd. for C₂₇H₃₄FN₅, 447.28; m/z found, 448.5[M+H]⁺. ¹H NMR (CDCl₃): 8.03-7.92 (m, 1H), 7.66-7.55 (m, 2H), 7.40-7.31(m, 2H), 7.24-7.17 (m, 1H), 6.54-6.43 (m, 1H), 3.45-3.36 (m, 2H),3.36-3.31 (m, 2H), 3.21-3.14 (m, 2H), 3.07-2.98 (m, 1H), 2.93-2.88 (m,2H), 2.33 (s, 3H), 1.60-1.53 (m, 9H), 1.37-1.31 (m, 6H).

Example 293:2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-carbonitrile

MS (ESI): mass calcd. for C₂₁H₁₇F₃N₆, 410.15; m/z found, 411.1 [M+H]⁺.¹H NMR (CDCl₃): 8.60 (s, 1H), 8.34 (dd, J=4.7, 1.9 Hz, 1H), 7.78 (dd,J=7.6, 1.9 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H),6.78-6.66 (m, 1H), 4.25-4.14 (m, 2H), 4.11-4.07 (m, 2H), 3.47-3.30 (m,2H), 3.20-3.13 (m, 2H).

Example 294:2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-carboxamidetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₁H₁₉F₃N₆O, 428.16; m/z found, 429.1 [M+H]⁺.¹H NMR (CD₃OD): 8.62 (s, 1H), 8.22 (dd, J=5.0, 1.9 Hz, 1H), 7.83 (dd,J=7.5, 1.9 Hz, 1H), 7.78 (d, J=8.7 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 6.89(dd, J=7.5, 5.0 Hz, 1H), 3.94-3.80 (m, 4H), 3.51-3.38 (m, 2H), 3.31-3.26(m, 2H).

Example 295:7-(3-Fluoropyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₀H₁₇F₄N₅, 403.14; m/z found, 404.2 [M+H]⁺.¹H NMR (CDCl₃): 8.62 (s, 1H), 8.11-7.79 (m, 2H), 7.77-7.62 (m, 4H),7.34-7.22 (m, 1H), 6.86-6.60 (m, 1H), 4.15-3.90 (m, 4H), 3.26-2.96 (m,4H).

Example 296:N-[4-(1,1-Dimethylethyl)phenyl]-7-[3-(ethylsulfonyl)pyridin-2-yl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared analogously to the methods described inExample 26, substituting 2-chloro-3-ethanesulfonyl-pyridine (preparedusing methods analogous to those reported in J. Org. Chem. 1979, 44(17),3080-3082) in Step C. MS (ESI): mass calcd. for C₂₈H₃₇N₅O₂S, 507.27; m/zfound, 508.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.44 (dd, J=4.7, 1.9 Hz, 1H), 8.27(dd, J=7.8, 1.9 Hz, 1H), 7.61-7.47 (m, 2H), 7.32-7.24 (m, 2H), 7.14 (dd,J=7.8, 4.8 Hz, 1H), 6.56 (s, 1H), 3.53-3.43 (m, 2H), 3.45-3.41 (m, 2H),3.22 (q, J=7.4 Hz, 2H), 3.15-3.08 (m, 2H), 3.01-2.92 (m, 1H), 2.91-2.86(m, 2H), 1.29-1.22 (m, 15H).

Example 297:7-[3-(Ethylsulfonyl)pyridin-2-yl]-2-piperidin-1-yl-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was prepared analogously to the methods described inExample 26, substituting 2-chloro-3-ethanesulfonyl-pyridine (preparedusing methods analogous to those reported in J. Org. Chem. 1979, 44(17),3080-3082) in Step C. MS (ESI): mass calcd. for C₂₇H₃₁F₃N₆O₂S, 560.22;m/z found, 561.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.44 (dd, J=4.7, 1.9 Hz, 1H),8.27 (dd, J=7.8, 1.9 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.7 Hz,2H), 7.13 (dd, J=7.8, 4.8 Hz, 1H), 6.60 (s, 1H), 3.76-3.58 (m, 4H),3.49-3.42 (m, 2H), 3.41-3.37 (m, 2H), 3.28 (q, J=7.4 Hz, 2H), 3.03-2.96(m, 2H), 2.85-2.78 (m, 2H), 1.65-1.49 (m, 4H), 1.02 (t, J=7.5 Hz, 3H).

The following Examples 298-302 were prepared using methods analogous tothose described in Example 26, substituting the appropriate 2-chloropyridines (see Cordi, A. A. et al. II Farmaco, 2002, 57, 787) in Step Cand anilines in Step E.

Example 298:2-(2-Piperidin-1-yl-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide

MS (ESI): mass calcd. for C₂₅H₂₈F₃N₇O₂S, 547.20; m/z found, 548.1[M+H]⁺. ¹H NMR (CDCl₃): 8.45 (dd, J=4.8, 1.9 Hz, 1H), 8.23 (dd, J=7.8,1.9 Hz, 1H), 7.57 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.15 (dd,J=7.8, 4.8 Hz, 1H), 6.60 (s, 1H), 3.72-3.61 (m, 4H), 3.46-3.38 (m, 2H),3.36-3.31 (m, 2H), 3.05-2.95 (m, 2H), 2.85-2.80 (m, 2H), 1.66-1.51 (m,4H).

Example 299:N-Cyclopropyl-2-(2-piperidin-1-yl-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide

MS (ESI): mass calcd. for C₂₈H₃₂F₃N₇O₂S, 587.23; m/z found, 588.1[M+H]⁺. ¹H NMR (CDCl₃): 8.44 (dd, J=4.8, 1.9 Hz, 1H), 8.26 (dd, J=7.8,1.9 Hz, 1H), 7.56 (d, J=8.6 Hz, 2H), 7.49 (d, J=8.8 Hz, 2H), 7.13 (dd,J=7.8, 4.8 Hz, 1H), 6.62 (s, 1H), 5.68-5.41 (m, 1H), 3.72-3.64 (m, 3H),3.46-3.39 (m, 2H), 3.36-3.32 (m, 2H), 3.03-2.93 (m, 2H), 2.84-2.78 (m,2H), 1.68-1.50 (m, 4H), 0.41-0.16 (m, 4H).

Example 300:N-(1-Methylethyl)-2-(2-piperidin-1-yl-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide

MS (ESI): mass calcd. for C₂₈H₃₄F₃N₇O₂S, 589.24; m/z found, 590.2[M+H]⁺. ¹H NMR (CDCl₃): 8.41 (dd, J=4.8, 1.9 Hz, 1H), 8.21 (dd, J=7.7,1.9 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.49 (d, J=8.6 Hz, 2H), 7.10 (dd,J=7.7, 4.8 Hz, 1H), 6.72 (s, 1H), 3.72-3.63 (m, 4H), 3.45-3.38 (m, 2H),3.36-3.31 (m, 2H), 3.11-3.02 (m, 1H), 3.00-2.95 (m, 2H), 2.86-2.79 (m,2H), 1.67-1.48 (m, 4H), 0.70 (d, J=6.5 Hz, 6H).

Example 301:7-[3-(Ethylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₂H₂₂F₃N₅O₂S, 477.14; m/z found, 478.1[M+H]⁺. ¹H NMR (CDCl₃): 8.63 (s, 1H), 8.55 (dd, J=4.7, 1.9 Hz, 1H), 8.35(dd, J=7.8, 1.8 Hz, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.65 (d, J=8.5 Hz, 2H),7.27-7.24 (m, 1H), 3.66-3.58 (m, 2H), 3.58-3.54 (m, 2H), 3.41-3.30 (m,2H), 3.17-3.06 (m, 4H), 1.04 (t, J=7.4 Hz, 3H).

Example 302:2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide

MS (ESI): mass calcd. for C₂₀H₁₉F₃N₆O₂S, 464.12; m/z found, 465.1[M+H]⁺. ¹H NMR (MeOD): 8.45-8.34 (m, 2H), 8.23 (dd, J=7.8, 1.8 Hz, 1H),7.63 (d, J=8.5 Hz, 2H), 7.52 (d, J=8.6 Hz, 2H), 7.15 (dd, J=7.8, 4.8 Hz,1H), 3.49-3.39 (m, 2H), 3.39-3.34 (m, 2H), 3.23-3.17 (m, 2H), 3.07-3.02(m, 2H).

Example 303: Methyl5-chloro-6-[2-(methylsulfanyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylate

Step A.4-Hydroxy-2-methylsulfanyl-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylicacid tert-butyl ester

To solution of 5-oxo-azepane-1,4-dicarboxylic acid 1-tert-butyl ester4-ethyl ester (10.5 g, 0.04 mol) in EtOH (168 mL) was added NaOEt (8.1g, 0.12 mol) and thiourea (4.2 g, 0.06 mol). The mixture was heated atreflux for 12 h. The mixture was cooled, treated with MeI (3.0 mL, 0.05mol) drop-wise, and stirred at rt for 1 h. The mixture was concentratedand the residue was dissolved in water and acidified to pH=7 with HOAc(a precipitate formed). The solid was filtered to give the titlecompound (8.4 g, 73%), which was used in the next step without furtherpurification.

Step B:2-Methylsulfanyl-4-trifluoromethanesulfonyloxy-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylicacid tert-butyl ester

To a solution of4-hydroxy-2-methylsulfanyl-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylicacid tert-butyl ester (1.2 g, 3.86 mmol) in THF (129 mL) was added KOtBu(518 mg, 4.63 mmol) at rt. After 20 min,N-phenyl-bis(trifluoromethanesulfonimide) (1.9 g, 5.40 mmol) was added.The reaction mixture was stirred for an additional 24 h at rt and thenconcentrated. The residue was purified (FCC) to afford the titlecompound (1.4 g, 82%)

Step C:(2-Methylsulfanyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine

A solution containingmethylsulfanyl-4-trifluoromethanesulfonyloxy-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylicacid tert-butyl ester (950 mg, 2.15 mmol), 4-trifluoromethylaniline (0.6mL, 4.74 mmol) and DMSO (8 mL) was heated at 100° C. for 24 h. Thereaction mixture was cooled to rt and diluted with water and extractedwith EtOAc. The combined organic extracts were dried and concentrated.The residue was purified (FCC; MeOH/CH₂Cl₂) to give the title compound(422 mg, 55%).

Step D

A solution of(2-methylsulfanyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine(187 mg, 0.53 mmol), 5,6-dichloro-nicotinic acid methyl ester (129 mg,0.58 mmol), and Et₃N (0.2 mL, 1.58 mmol) in DMF (1.2 mL) was heated at120° C. for 2 h. The mixture was cooled to rt, diluted with water, andextracted with EtOAc. The combined organic layers were dried andconcentrated. The residue was purified (FCC) to give the title compound(203 mg, 74%). MS (ESI): mass calcd. for C₂₃H₂₁ClF₃N₅O₂S, 523.11; m/zfound, 524.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.57 (d, J=2.0 Hz, 1H), 8.00 (d,J=2.0 Hz, 1H), 7.59 (d, J=8.6 Hz, 2H), 7.48 (d, J=8.6 Hz, 2H), 6.73-6.59(m, 1H), 3.89-3.65 (m, 7H), 3.19-3.07 (m, 2H), 2.95-2.87 (m, 2H), 2.40(s, 3H).

The following Examples 304-306 were prepared using methods analogous tothose described in Example 303, substituting the appropriate anilines inStep C and 2-chloro pyridines in Step D.

Example 304:2-(Methylsulfanyl)-7-[3-(methylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₂H₂₂F₃N₅O₂S₂, 509.11; m/z found, 510.1[M+H]⁺. ¹H NMR (CDCl₃): 8.62-8.49 (m, 1H), 8.40-8.35 (m, 1H), 7.73 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.25 (dd, J=7.8, 4.7 Hz, 1H),7.05-6.94 (m, 1H), 3.61-3.54 (m, 2H), 3.55-3.50 (m, 2H), 3.28-3.17 (m,2H), 3.06 (s, 3H), 3.04-2.99 (m, 2H), 2.55 (s, 3H).

Example 305:[7-(3-Ethanesulfonyl-pyridin-2-yl)-2-methylsulfanyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

MS (ESI): mass calcd. for C₂₃H₂₄F₃N₅O₂S₂, 523.13; m/z found, 524.1[M+H]⁺. ¹H NMR (CDCl₃): 8.62-8.46 (m, 1H), 8.38-8.31 (m, 1H), 7.72 (d,J=8.5 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.26-7.22 (m, 1H), 3.63-3.42 (m,4H), 3.30-3.17 (m, 4H), 3.05-2.96 (m, 2H), 2.54 (s, 3H), 1.10-1.05 (m,3H).

Example 306:{5-Chloro-6-[2-(methylsulfanyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridin-3-yl}methanol

The title compound was prepared analogously to that reported startingmethyl5-chloro-6-[2-(methylsulfanyl)-4-{[4-(trifluoromethyl)-phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylate(Example 303) (Boechat, N. et al. Tetrahedron Lett. 2004, 45, 6021). MS(ESI): mass calcd. for C₂₂H₂₁ClF₃N₅OS, 495.11; m/z found, 496.1 [M+H]⁺.¹H NMR (MeOD): 8.38-8.26 (m, 1H), 8.03 (d, J=8.6 Hz, 2H), 7.96-7.92 (m,1H), 7.80 (d, J=8.6 Hz, 2H), 4.79-4.69 (m, 2H), 3.86-3.69 (m, 4H),3.41-3.27 (m, 4H), 2.68 (s, 3H).

Example 307:2-({[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}oxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

A dispersion of NaH in mineral oil (12.0 mg, 0.28 mmol) was added to aflask containing (2,2-dimethyl-[1,3]dioxolan-4-yl)-methanol (116 μL,0.94 mmol) and DMF (1.0 mL). After 30 min, the mixture was transferredto a flask containing[2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine(Example 53; 50 mg, 0.094 mmol). The resulting mixture was then heatedat 70° C. for 24 h. The mixture was cooled, diluted with MeOH (1.0 mL)and purified by reverse phase HPLC, yielding 39 mg (70%) of the titlecompound. MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅O₃, 583.20; m/z found,584.2 [M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.69(d, J=11.0 Hz, 2H), 7.59 (d, J=11.0 Hz, 2H), 6.98-6.94 (m, 1H), 6.68 (s,1H), 4.52-4.56 (m, 1H), 4.42-4.38 (m, 1H), 4.28-4.24 (m, 1H), 4.16-4.12(m, 1H), 3.94-3.90 (m, 1H), 3.63-3.56 (m, 4H), 3.18-3.15 (m, 2H),2.96-2.93 (m, 2H), 1.46 (s, 3H), 1.38 (s, 3H).

The following Examples 308-340 were prepared using methods analogous tothose described in Example 307, substituting the appropriate alcohols.

Example 308:2-(Cyclohexyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅O₃S, 615.17; m/z found, 616.2[M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.38 (d, J=5.0 Hz, 1H), 7.98 (d, J=9.0 Hz,2H), 7.93-7.87 (m, 3H), 7.00-6.97 (m, 1H), 6.96 (s, 1H), 4.92-4.87 (m,1H), 3.64-3.57 (m, 4H), 3.22-3.18 (m, 2H), 3.00-2.95 (m, 2H), 2.11-2.08(m, 2H), 1.89-1.86 (m, 2H), 1.69-1.63 (m, 2H), 1.46-1.25 (m, 4H).

Example 309:2-[(1-Cyclohexylethyl)oxy]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₀H₃₃F₆N₅O, 593.26; m/z found, 594.3 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 8.08 (d, J=11.0 Hz, 1H), 7.89-7.86(m, 1H), 7.46 (s, 2H), 6.97-6.94 (m, 1H), 6.42 (s, 1H), 4.84-4.78 (m,1H), 3.66-3.53 (m, 4H), 3.19-3.16 (m, 2H), 2.94-2.91 (m, 2H), 2.36 (s,3H), 1.80-1.72 (m, 4H), 1.68-1.57 (m, 2H), 1.24 (d, J=8.0 Hz, 3H),1.21-0.97 (m, 5H).

Example 310:2-(Cyclopentyloxy)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅O, 551.21; m/z found, 552.3 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 8.17 (d, J=11.0 Hz, 1H), 7.89-7.87(m, 1H), 7.46 (s, 2H), 6.97-6.94 (m, 1H), 6.44 (s, 1H), 5.25-5.20 (m,1H), 3.66-3.57 (m, 4H), 3.18-3.15 (m, 2H), 2.95-2.92 (m, 2H), 2.36 (s,3H), 1.88-1.76 (m, 6H), 1.63-1.54 (m, 2H).

Example 311:2-[(1-Methylpiperidin-4-yl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₈F₆N₆O, 566.22; m/z found, 567.3 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 2H), 7.88-7.86 (m, 1H), 7.60 (s, 3H),7.00-6.97 (m, 1H), 5.24 (br s, 1H), 3.57-3.52 (m, 4H), 3.46-3.05 (m,6H), 3.05-3.02 (m, 2H), 2.79 (s, 3H), 2.65 (s, 1H), 2.37-2.30 (m, 2H),2.18-2.13 (m, 2H).

Example 312:N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅O₂, 567.21; m/z found, 568.2 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.38 (m, 1H), 8.01 (d, J=10.5 Hz, 1H), 7.89-7.86(m, 1H), 7.48-7.46 (m, 2H), 6.98-6.95 (m, 1H), 6.43 (s, 1H), 4.99-4.92(m, 1H), 4.02-3.96 (m, 2H), 3.90 (s, 1H), 3.65-3.57 (m, 4H), 3.53-3.47(m, 2H), 3.19-3.16 (m, 2H), 2.96-2.93 (m, 2H), 2.36 (s, 2H), 2.03-1.98(m, 2H), 1.86-1.77 (m, 2H).

Example 313:N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₆N₅O₂, 553.19; m/z found, 554.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.97 (d, J=11.0 Hz, 1H), 7.89-7.86(m, 1H), 7.49 (s, 2H), 6.98-6.95 (m, 1H), 6.42 (s, 1H), 5.33-5.28 (m,1H), 3.97-3.85 (m, 4H), 3.66-3.57 (m, 4H), 3.19-3.16 (m, 2H), 2.96-2.93(m, 2H), 2.35 (s, 3H), 2.20-2.08 (m, 2H).

Example 314:N-[4-(Pyrrolidin-1-ylsulfonyl)phenyl]-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₃₁F₃N₆O₄S, 604.21; m/z found, 605.2[M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.89-7.87 (m, 1H), 7.79 (d,J=11.0 Hz, 2H), 7.72 (d, J=11.0 Hz, 2H), 6.99-6.96 (m, 1H), 6.81 (s,1H), 5.46-5.42 (m, 1H), 4.70-3.90 (m, 4H), 3.63-3.56 (m, 4H), 3.27-3.24(m, 4H), 3.19-3.16 (m, 2H), 2.98-2.95 (m, 2H), 2.25-2.20 (m, 2H),1.80-1.76 (m, 4H).

Example 315:2-{[1-(1-Methylethyl)pyrrolidin-3-yl]oxy}-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₃₀F₆N₆O, 580.24; m/z found, 581.3 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.90-7.88 (m, 1H), 7.70 (d, J=9.0 Hz,2H), 7.61 (d, J=9.0 Hz, 2H), 6.99-6.96 (m, 1H), 6.67 (s, 1H), 5.37-5.33(m, 1H), 3.65-3.58 (m, 4H), 3.31-3.28 (m, 1H), 3.20-3.17 (m, 2H),2.97-2.94 (m, 2H), 2.83-2.79 (m, 1H), 2.69-2.62 (m, 2H), 2.47-2.42 (m,1H), 2.34-2.27 (m, 1H), 2.08-2.02 (m, 1H), 1.12-1.10 (m, 6H).

Example 316:2-[(1-Cyclohexylethyl)oxy]-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₂H₃₉F₃N₆O, 580.31; m/z found, 581.4 [M+H]⁺.

Example 317:2-[(1-Cyclopropylethyl)oxy]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₆N₅O₃S, 601.16; m/z found, 602.2[M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.97 (d, J=9.0 Hz, 2H),7.90-7.88 (m, 1H), 7.88 (d, J=9.0 Hz, 2H), 7.00-6.97 (m, 1H), 6.95 (s,1H), 4.64-4.58 (m, 1H), 3.63-3.57 (m, 4H), 3.21-3.19 (m, 2H), 3.00-2.98(m, 2H), 1.45 (d, J=1.5 Hz, 3H), 1.24-1.17 (m, 1H), 0.61-0.51 (m, 2H),0.47-0.42 (m, 1H), 0.34-0.29 (m, 1H).

Example 318:2-[(1-Cyclohexylethyl)oxy]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₁F₆N₅O₃S, 643.21; m/z found, 644.2[M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.98 (d, J=9.0 Hz, 2H),7.92-7.88 (m, 1H), 7.90 (d, J=9.0 Hz, 2H), 7.00-6.98 (m, 1H), 6.95 (s,1H), 4.95-4.90 (m, 1H), 3.63-3.58 (m, 4H), 3.22-3.20 (m, 2H), 3.00-2.97(m, 2H), 1.91-1.88 (m, 1H), 1.83-1.76 (m, 3H), 1.72-1.66 (m, 2H), 1.33(d, J=1.5 Hz, 3H), 1.30-1.08 (m, 5H).

Example 319:2-(Cyclopentyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₆N₅O₃S, 601.16; m/z found, 602.2[M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.99 (d, J=9.0 Hz, 2H), 7.94(d, J=9.0 Hz, 2H), 7.90-7.88 (m, 1H), 7.00-6.97 (m, 1H), 6.97 (s, 1H),5.37-5.33 (m, 1H), 3.63-3.57 (m, 4H), 3.22-3.19 (m, 2H), 3.00-2.98 (m,2H), 2.00-1.91 (m, 4H), 1.91-1.85 (m, 2H), 1.69-1.63 (m, 2H).

Example 320:2-[(1-Cyclohexylethyl)oxy]-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₂H₃₉F₃N₆O₃S, 644.28; m/z found, 645.5[M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.89-7.86 (m, 1H), 7.80 (d,J=9.0 Hz, 2H), 7.74 (d, J=9.0 Hz, 2H), 6.96 (m, 1H), 6.75 (s, 1H),4.93-4.87 (m, 1H), 3.62-3.54 (m, 4H), 3.27-3.23 (m, 4H), 3.19-3.16 (m,2H), 2.95-2.93 (m, 2H), 1.89-1.85 (m, 1H), 1.82-1.71 (m, 7H), 1.68-1.62(m, 2H), 1.29 (d, J=1.5 Hz, 3H), 1.27-1.04 (m, 5H).

Example 321:2-[(1-Cyclopropylethyl)oxy]-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₂H₃₉F₃N₆O, 580.7; m/z found, 581.4 [M+H]⁺.

Example 322:2-(Tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₆N₅O₄S, 617.15; m/z found, 618.2[M+H]⁺. ¹H NMR (CDCl₃): 8.41-8.40 (m, 1H), 7.99 (d, J=9.0 Hz, 2H),7.91-7.87 (m, 3H), 7.01-6.98 (m, 1H), 6.95 (s, 1H), 5.16-5.11 (m, 1H),4.07-4.03 (m, 2H), 3.64-3.58 (m, 6H), 3.23-3.21 (m, 2H), 3.01-2.99 (m,2H), 2.13-2.08 (m, 2H), 1.94-1.87 (m, 2H).

Example 323:N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₃₁F₃N₆O₂, 540.24; m/z found, 541.3 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.89-7.87 (m, 1H), 6.97-6.94 (m, 1H),6.92 (d, J=8.0 Hz, 1H), 6.81-6.79 (m, 1H), 6.60 (d, J=2.0 Hz, 1H), 6.44(s, 1H), 5.45-5.42 (m, 1H), 4.10-4.06 (m, 1H), 4.00-3.95 (m, 1H),3.93-3.88 (m, 2H), 3.65-3.58 (m, 4H), 3.26-3.23 (m, 2H), 3.16-3.14 (m,2H), 2.92-2.89 (m, 4H), 2.76 (t, J=6.0 Hz, 2H), 2.23-2.13 (m, 3H),2.02-1.97 (m, 2H).

Example 324:2-(Cyclopentyloxy)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₃F₃N₆O, 538.27; m/z found, 539.3 [M+H]⁺.

Example 325:2-[(1-Cyclopropylethyl)oxy]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅O, 551.21; m/z found, 552.3 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 8.03 (d, J=11.5 Hz, 1H), 7.89-7.86(m, 1H), 7.47 (s, 1H), 7.45 (s, 1H), 6.97-6.94 (m, 1H), 6.39 (s, 1H),4.52-4.45 (m, 1H), 3.65-3.57 (m, 4H), 3.18-3.15 (m, 2H), 2.93-2.90 (m,2H), 2.35 (s, 3H), 1.37 (d, J=8.0 Hz, 3H), 1.18-1.09 (m, 1H), 0.55-0.43(m, 2H), 0.40-0.33 (m, 1H), 0.25-0.19 (m, 1H).

Example 326:2-(Cyclohexyloxy)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₂₉F₆N₅O, 565.23; m/z found, 566.3 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 8.16 (d, J=9.0 Hz, 1H), 7.90-7.88 (m,1H), 7.49-7.48 (m, 2H), 6.99-6.96 (m, 1H), 6.46 (s, 1H), 4.81-4.76 (m,1H), 3.67-3.65 (m, 2H), 3.61-3.59 (m, 2H), 3.20-3.17 (m, 2H), 2.96-2.94(m, 2H), 2.38 (s, 3H), 2.05-2.01 (m, 2H), 1.85-1.80 (m, 2H), 1.63-1.51(m, 1H), 1.38-1.27 (m, 5H).

Example 327:2-(Butyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₄F₆N₆O, 526.19; m/z found, 527.2 [M+H]⁺.¹H NMR (CDCl₃): 8.82 (d, J=2.5 Hz, 1H), 8.39-8.34 (m, 2H), 7.89-7.87 (m,1H), 7.67 (d, J=8.5 Hz, 1H), 6.98-6.95 (m, 1H), 6.83 (br s, 1H), 4.29(t, J=6.5 Hz, 2H), 3.64-3.61 (m, 2H), 3.59-3.56 (m, 2H), 3.21-3.19 (m,2H), 3.01-2.98 (m, 2H), 1.80-1.74 (m, 2H), 1.55-1.47 (m, 2H), 0.96 (t,J=7.0 Hz, 3H).

Example 328:2-(Cyclohexyloxy)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₀H₃₅F₃N₆O, 552.28; m/z found, 553.3 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.87-7.84 (m, 1H), 6.94-6.88 (m, 3H),6.56 (d, J=2.5 Hz, 1H), 6.41 (s, 1H), 4.93-4.86 (m, 1H), 3.63-3.56 (m,4H), 3.23 (t, J=7.0 Hz, 2H), 3.14-3.11 (m, 2H), 2.89 (s, 3H), 2.88-2.86(m, 2H), 2.74 (t, J=8.0 Hz, 2H), 2.0-1.94 (m, 4H), 1.81-1.78 (m, 2H),1.59-1.53 (m, 3H), 1.37-1.26 (m, 3H).

Example 329:N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₃F₃N₆O₂, 554.26; m/z found, 555.3 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.89-7.87 (m, 1H), 6.97-6.94 (m, 1H),6.91 (d, J=8.0 Hz, 1H), 6.86-6.83 (m, 1H), 6.59 (d, J=2.0 Hz, 1H), 6.43(s, 1H), 5.13-5.08 (m, 1H), 4.03-3.99 (m, 2H), 3.65-3.53 (m, 6H),3.26-3.24 (m, 2H), 3.17-3.14 (m, 2H), 2.92-2.89 (m, 5H), 2.76 (t, J=6.5Hz, 2H), 2.08-1.97 (m, 4H), 1.89-1.81 (m, 2H).

Example 330:2-({[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}oxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅O₃, 583.20; m/z found, 584.2 [M+H]⁺.¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.69 (d, J=11.0Hz, 2H), 7.59 (d, J=11.0 Hz, 2H), 6.98-6.94 (m, 1H), 6.68 (s, 1H),4.52-4.56 (m, 1H), 4.42-4.38 (m, 1H), 4.28-4.24 (m, 1H), 4.16-4.12 (m,1H), 3.94-3.90 (m, 1H), 3.63-3.56 (m, 4H), 3.18-3.15 (m, 2H), 2.96-2.93(m, 2H), 1.46 (s, 3H), 1.38 (s, 3H).

Example 331:2-(Tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₃F₆N₅O₄S, 603.14; m/z found, 604.2[M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.39 (m, 1H), 7.99 (d, J=9.0 Hz, 2H),7.91-7.87 (m, 3H), 7.01-6.98 (m, 2H), 5.50-5.46 (m, 1H), 4.12-4.08 (m,1H), 4.06-3.93 (m, 3H), 3.64-3.58 (m, 4H), 3.23-3.20 (m, 2H), 3.02-2.99(m, 2H), 2.28-2.24 (m, 2H).

Example 332:2-[(1-Cyclohexylethyl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₁F₆N₅O, 579.24; m/z found, 580.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.90-7.88 (m, 1H), 7.70 (d, J=8.5 Hz,2H), 7.59 (d, J=8.5 Hz, 2H), 6.99-6.96 (m, 1H), 6.67 (s, 1H), 4.94-4.88(m, 1H), 3.65-3.58 (m, 4H), 3.20-3.17 (m, 2H), 2.96-2.94 (m, 2H),1.90-1.87 (m, 1H), 1.83-1.75 (m, 3H), 1.72-1.65 (m, 2H), 1.31 (d, J=6.5Hz, 3H), 1.28-1.07 (m, 5H).

Example 333:2-(Cyclopentyloxy)-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₃F₃N₆O₃S, 602.23; m/z found, 603.3[M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.79 (s,4H), 6.98-6.94 (m, 1H), 6.77 (s, 1H), 5.33-5.30 (m, 1H), 3.62-3.55 (m,4H), 3.27-3.23 (m, 4H), 3.18-3.16 (m, 2H), 2.96-2.93 (m, 2H), 1.96-1.75(m, 9H), 1.66-1.58 (m, 3H).

Example 334:2-[(1-Cyclopropylethyl)oxy]-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₃F₃N₆O₃S, 602.23; m/z found, 603.3[M+H]⁺. ¹H NMR (CDCl₃): 8.39-8.37 (m, 1H), 7.89-7.86 (m, 1H), 7.78 (d,J=11.0 Hz, 2H), 7.71 (d, J=11.0 Hz, 2H), 6.98-6.94 (m, 1H), 6.74 (s,1H), 4.61-4.54 (m, 1H), 3.62-3.55 (m, 4H), 3.27-3.23 (m, 4H), 3.18-3.15(m, 2H), 2.95-2.93 (m, 2H), 1.79-1.75 (m, 4H), 1.42 (d, J=8.0 Hz, 3H),1.21-1.15 (m, 1H), 0.58-0.39 (m, 3H), 0.30-0.24 (m, 1H).

Example 335:N-[4-(Pyrrolidin-1-ylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₃F₃N₆O₄S, 618.22; m/z found, 619.3[M+H]⁺. ¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.89-7.86 (m, 1H), 7.79 (d,J=11.0 Hz, 2H), 7.72 (d, J=11.0 Hz, 2H), 6.99-6.95 (m, 1H), 6.80 (s,1H), 5.13-5.06 (m, 1H), 4.06-4.00 (m, 2H), 3.62-3.54 (m, 6H), 3.27-3.24(m, 4H), 3.19-3.16 (m, 2H), 2.97-2.94 (m, 2H), 2.11-2.06 (m, 2H),1.92-1.83 (m, 2H), 1.80-1.75 (m, 4H).

Example 336:2-(Cycloheptyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₂₉F₆N₅O, 565.23; m/z found, 566.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.90-7.88 (m, 1H), 7.71 (d, J=9.0 Hz,2H), 7.60 (d, J=9.0 Hz, 2H), 6.99-6.96 (m, 1H), 6.68 (s, 1H), 5.08-5.03(m, 1H), 3.65-3.58 (m, 4H), 3.19-3.17 (m, 2H), 2.96-2.94 (m, 2H),2.13-2.07 (m, 2H), 1.88-1.74 (m, 4H), 1.64-1.58 (m, 4H), 1.51-1.44 (m,2H).

Example 337:2-(Cyclopentyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₆N₅O, 537.20; m/z found, 538.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.90-7.87 (m, 1H), 7.74 (d, J=8.5 Hz,2H), 7.60 (d, J=8.5 Hz, 2H), 6.99-6.96 (m, 1H), 6.70 (s, 1H), 5.34-5.30(m, 1H), 3.64-3.57 (m, 4H), 3.19-3.17 (m, 2H), 2.97-2.94 (m, 2H),1.97-1.92 (m, 4H), 1.88-1.83 (2H), 1.65-1.62 (m, 2H).

Example 338:2-(Cyclohexyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅O, 551.21; m/z found, 552.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.39 (m, 1H), 7.90-7.87 (m, 1H), 7.72 (d, J=8.5 Hz,2H), 7.59 (d, J=8.5 Hz, 2H), 6.98-6.96 (m, 1H), 6.71 (s, 1H), 4.90-4.84(m, 1H), 3.64-3.57 (m, 4H), 3.19-3.17 (m, 2H), 2.96-2.94 (m, 2H),2.10-2.07 (m, 2H), 1.88-1.84 (m, 2H), 1.65-1.55 (m, 3H), 1.44-1.27 (m,3H).

Example 339:2-(Tetrahydro-2H-pyran-4-yloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₆H₂₅F₆N₅O₂, 553.19; m/z found, 554.2 [M+H]⁺.¹H NMR (CDCl₃): 8.41-8.40 (m, 1H), 7.91-7.88 (m, 1H), 7.68 (d, J=8.5 Hz,2H), 7.60 (d, J=8.5 Hz, 2H), 6.99-6.96 (m, 1H), 6.69 (s, 1H), 5.12-5.06(m, 1H), 4.06-4.02 (m, 2H), 3.97 (s, 1H), 3.65-3.56 (m, 5H), 3.20-3.18(m, 2H), 2.97-2.95 (m, 2H), 2.11-2.04 (m, 2H), 1.93-1.85 (m, 2H).

Example 340:2-(Tetrahydrofuran-3-yloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₃F₆N₅O₂, 539.18; m/z found, 540.2 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.38 (m, 1H), 7.89-7.86 (m, 1H), 7.65 (d, J=11.0Hz, 2H), 7.60 (d, J=11.0 Hz, 2H), 6.98-6.95 (m, 1H), 6.67 (s, 1H),5.43-5.39 (m, 1H), 4.09-4.05 (m, 1H), 4.00-3.89 (m, 3H), 3.64-3.56 (m,4H), 3.19-3.15 (m, 2H), 2.96-2.93 (m, 2H), 2.24-2.17 (m, 2H).

The following Examples 341-343 were prepared using methods analogous tothose described in Example 307, substituting the appropriate alcoholsand using the appropriate alcohol as the solvent.

Example 341:2-[(1-Methylethyl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅O, 511.18; m/z found, 512.5 [M+H]⁺.¹H NMR (MeOD): 8.46-8.44 (m, 1H), 8.03 (dd, J=7.8, 1.7 Hz, 1H), 7.74 (s,4H), 7.17-7.12 (m, 1H), 5.22-5.16 (m, 1H), 3.65-3.61 (m, 2H), 3.60-3.56(m, 2H), 3.26-3.21 (m, 2H), 3.19-3.14 (m, 2H), 1.37 (d, J=6.2 Hz, 6H).

Example 342:2-(Phenyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

MS (ESI): mass calcd. for C₂₇H₂₁F₆N₅O, 545.17; m/z found, 546.5 [M+H]⁺.¹H NMR (MeOD): 8.48-8.46 (m, 1H), 8.04 (dd, J=7.8, 1.7 Hz, 1H),7.51-7.46 (m, 2H), 7.44 (d, J=8.6 Hz, 2H), 7.40-7.34 (m, 3H), 7.24 (d,J=7.7 Hz, 2H), 7.16 (dd, J=7.7, 4.8 Hz, 1H), 3.69-3.64 (m, 2H),3.61-3.55 (m, 2H), 3.35-3.31 (m, 2H), 3.21-3.16 (m, 2H).

Example 343:2-(Butyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₅O, 525.20; m/z found, 526.1 [M+H]⁺.¹H NMR (CDCl₃): 8.40-8.37 (m, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.72-7.69 (m, 2H), 7.61-7.57 (m, 2H), 6.98-6.94 (m, 1H), 6.66 (s, 1H),4.29 (t, J=6.6 Hz, 2H), 3.64-3.56 (m, 4H), 3.20-3.15 (m, 2H), 2.97-2.94(m, 2H), 1.81-1.75 (m, 2H), 1.54-1.47 (m, 2H), 0.96 (t, J=7.4 Hz, 3H).

Example 344:4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-oltrifluoroacetic acid salt

A solution of[2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine(Example 53; 112 mg, 0.21 mmol) and NaOH (25 mg, 0.63 mmol) in 1:3H₂O/dioxane (4 mL) was heated at 60° C. for 1 h. The mixture was cooled,acidified with TFA (3 drops), and directly purified using PreparativeHPLC (conditions as in Example 54) to give the title compound (60 mg,98%). MS (ESI): mass calcd. for C₂₁H₁₇F₆N₅O, 469.13; m/z found, 470.5[M+H]⁺. ¹H NMR (CDCl₃): 8.46-8.41 (m, 1H), 7.97 (dd, J=7.8, 1.5 Hz, 1H),7.64 (s, 4H), 7.09 (dd, J=7.7, 4.9 Hz, 1H), 3.63-3.58 (m, 2H), 3.58-3.53(m, 2H), 3.18-3.12 (m, 2H), 2.89-2.84 (m, 2H).

Example 345:2-(Ethyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

The title compound was prepared using methods analogous to thosedescribed in Example 62. MS (ESI): mass calcd. for C₂₃H₂₁F₆N₅O, 497.17;m/z found, 498.4 [M+H]⁺. ¹H NMR (MeOD): 8.45 (dd, J=4.7, 1.5 Hz, 1H),8.03 (dd, J=7.8, 1.8 Hz, 1H), 7.75 (q, J=8.9 Hz, 4H), 7.15 (dd, J=7.5,4.8 Hz, 1H), 4.45 (q, J=7.1 Hz, 2H), 3.64-3.61 (m, 2H), 3.59-3.56 (m,2H), 3.25-3.22 (m, 2H), 3.17-3.15 (m, 2H), 1.38 (t, J=7.1 Hz, 3H).

Example 346:2-[(Methyloxy)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt

The title compound was prepared using methods analogous to thosedescribed for Example 39 with modifications to Step A as follows:

Step A.2-Hydroxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol

To solution of NaOMe (1.9 mL) in MeOH (0.5 mL) was added5-oxo-1-(3-trifluoromethyl-pyridin-2-yl)-azepane-4-carboxylic acid ethylester (Intermediate B; 285 mg, 0.96 mmol), followed by2-chloro-acetamidine (149 mg, 1.16 mmol). After heating at 100° C. in amicrowave for 15 min, the mixture was cooled and concentrated. Theresidue was dissolved in water and extracted with CH₂Cl₂. The combinedorganic layers were dried, concentrated, and directly purified usingPreparative HPLC (conditions as in Example 54) to give the titlecompound (86 mg, 26%). MS (ESI): mass calcd. for C₂₂H₂₀F₆N₆O, 498.16;m/z found, 499.3 [M+H]⁺. ¹H NMR (MeOD): 8.95 (d, J=2.3 Hz, 1H),8.47-8.45 (m, 1H), 8.29 (dd, J=8.5, 2.2 Hz, 1H), 8.04 (dd, J=7.8, 1.7Hz, 1H), 7.88 (d, J=8.6 Hz, 1H), 7.16 (dd, J=7.7, 4.9 Hz, 1H), 4.61 (s,2H), 3.68-3.61 (m, 4H), 3.53 (s, 3H), 3.49-3.45 (m, 2H), 3.30-3.28 (m,2H).

Example 347:2-Methyl-2-[4-({2-[(methyloxy)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanenitriletrifluoroacetic acid salt

The title compound was prepared using methods analogous to thosedescribed in Example 346, substituting the appropriate anilines in StepE. MS (ESI): mass calcd. for C₂₆H₂₇F₃N₆O, 496.22; m/z found, 497.5[M+H]⁺. ¹H NMR (MeOD): 8.45 (dd, J=4.7, 1.4 Hz, 1H), 8.03 (dd, J=7.8,1.8 Hz, 1H), 7.58 (s, 4H), 7.14 (dd, J=7.4, 4.8 Hz, 1H), 4.54 (s, 2H),3.68-3.60 (m, 4H), 3.51 (s, 3H), 3.44-3.40 (m, 2H), 3.25-3.21 (m, 2H),1.75 (s, 6H).

Example 348:2-(Methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

The title compound was synthesized in a manner similar to Example 53with modifications to Step C in Example 52 as follows:

Step C

To a solution of4-chloro-2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine(400 mg, 1.07 mmol), 4-trifluoromethyl-amino-pyridine (208 mg, 1.28mmol), and NaOtBu (144 mg, 1.5 mmol) in toluene (4 mL) in a microwavevial was added a solution of Pd(OAc)₂ (3.7 mg, 0.016 mmol) and2-(dicyclohexylphosphino)biphenyl (DCPB) (11.9 mg, 0.034 mmol) intoluene (1 mL). The mixture was flushed with N_(2(g)) and heated in amicrowave at 200° C. for 2 h. The mixture was cooled, filtered through aplug of diatomaceous earth, and concentrated. The residue was purified(FCC) to afford the title compound (230 mg, 48%). MS (ESI): mass calcd.for C₂₁H₁₈F₆N₆O₂S, 532.11; m/z found, 533.1 [M+H]⁺. ¹H NMR (CDCl₃): 8.67(d, J=8.9 Hz, 1H), 8.56-8.54 (m, 1H), 8.42-8.40 (m, 1H), 8.03-8.00 (m,1H), 7.89 (dd, J=7.8, 1.8 Hz, 1H), 7.85 (s, 1H), 7.03-6.98 (m, 1H),3.70-3.65 (m, 2H), 3.63-3.59 (m, 2H), 3.39-3.36 (m, 2H), 3.32 (s, 3H),3.19-3.15 (m, 2H).

Example 349:2-(Phenylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

To a microwave reaction vial were added[2-methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine(53 mg, 0.1 mmol), thiophenol (16 mg, 0.15 mmol), p-toluenesulfonic acidmonohydrate (10 mg, 0.05 mmol), and DMF (0.4 mL). The vial was capped,and the mixture was heated via microwave irradiation at 100° C. for 10min, filtered through a 0.45 μm filter, and the filtrate was purified byreversed phase HPLC (Phenomenex Gemini 30 mm×100 mm column, gradient ofacetonitrile in 20 mM aqueous NH₄OH). The title compound was obtained asa white solid (27 mg, 48%). MS (ESI): mass calcd. for C₂₇H₂₁F₆N₅S,561.14; m/z found, 562 [M+H]⁺. ¹H NMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz,1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.68-7.62 (m, 2H), 7.56-7.50 (m, 1H),7.50-7.42 (m, 2H), 7.23 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 6.96(dd, J=7.4, 4.6 Hz, 1H), 6.58 (bs, 1H), 3.66-3.55 (m, 4H), 3.23-3.17 (m,2H), 2.96-2.90 (m, 2H).

Examples 350-352 were synthesized in a manner similar to Example 349substituting the appropriate thiols.

Example 350:2-(Phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₁F₆N₅O₂S₂, 625.10; m/z found, 626 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.7, 1.4 Hz, 1H), 7.89 (dd, J=7.8, 1.8 Hz,1H), 7.70-7.64 (m, 2H), 7.63-7.53 (m, 3H), 7.50-7.44 (m, 2H), 6.98 (dd,J=7.9, 5.0 Hz, 1H), 6.81 (bs, 1H), 3.65-3.53 (m, 4H), 3.25-3.18 (m, 2H),3.00-2.92 (m, 2H).

Example 351:N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₂₃F₆N₅S, 575.16; m/z found, 576 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.7, 1.4 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.61-7.56 (m, 2H), 7.48-7.42 (m, 2H), 7.42-7.33 (m, 2H), 7.32-7.28 (m,1H), 7.02-6.93 (m, 2H), 6.43 (bs, 1H), 3.70-3.62 (m, 2H), 3.62-3.56 (m,2H), 3.23-3.16 (m, 2H), 2.97-2.91 (m, 2H), 2.22 (s, 3H).

Example 352:2-(Phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₂H₃₃F₃N₆S, 590.24; m/z found, 591 [M+H]⁺. ¹HNMR (CDCl₃): 8.37 (dd, J=4.7, 1.6 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.66-7.60 (m, 2H), 7.43-7.33 (m, 3H), 6.94 (dd, J=7.7, 4.8 Hz, 1H), 6.77(d, J=8.3 Hz, 1H), 6.53 (dd, J=8.3, 2.2 Hz, 1H), 6.35 (bs, 1H), 6.23 (d,J=2.2 Hz, 1H), 3.65-3.54 (m, 4H), 3.22-3.10 (m, 4H), 2.91-2.83 (m, 2H),2.77 (s, 3H), 1.76-1.70 (m, 2H), 1.25 (s, 6H).

Examples 353-375 were synthesized in a manner similar to Example 349substituting the appropriate thiols and substituting Cs₂CO₃ (4 molarequivalents) for p-toluenesulfonic acid.

Example 353:2-[(Phenylmethyl)sulfanyl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₂₃F₆N₅S, 575.16; m/z found, 576 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.59 (d, J=8.6 Hz, 2H), 7.52 (d, J=8.7 Hz, 2H), 7.37-7.32 (m, 2H),7.30-7.20 (m, 3H), 6.96 (dd, J=7.4, 4.8 Hz, 1H), 6.62 (bs, 1H), 4.36 (s,2H), 3.67-3.60 (m, 2H), 3.60-3.54 (m, 2H), 3.21-3.15 (m, 2H), 2.98-2.91(m, 2H).

Example 354:2-(Cyclohexylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅S, 567.19; m/z found, 568 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.67 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 6.96 (dd, J=7.5, 4.6 Hz,1H), 6.63 (bs, 1H), 3.73-3.61 (m, 1H), 3.68-3.60 (m, 2H), 3.60-3.53 (m,2H), 3.19-3.12 (m, 2H), 2.98-2.92 (m, 2H), 2.14-2.05 (m, 2H), 1.82-1.73(m, 2H), 1.68-1.60 (m, 1H), 1.56-1.43 (m, 2H), 1.43-1.23 (m, 3H).

Example 355:2-[(1-Methylethyl)sulfanyl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅S, 527.16; m/z found, 528 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 7.87 (dd, J=7.8, 1.8 Hz, 1H),7.68 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 6.96 (dd, J=7.8, 5.1 Hz,1H), 6.63 (bs, 1H), 3.87 (sept, J=6.8 Hz, 1H), 3.67-3.61 (m, 2H),3.61-3.54 (m, 2H), 3.20-3.14 (m, 2H), 2.98-2.92 (m, 2H), 1.41 (d, J=6.8Hz, 6H).

Example 356:1-[(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)sulfanyl]propan-2-ol

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅OS, 543.15; m/z found, 544 [M+H]⁺.¹H NMR (CDCl₃): 8.39 (dd, J=4.7, 1.5 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz,1H), 7.65 (d, J=8.8 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 6.97 (dd, J=7.5,4.7 Hz, 1H), 6.67 (bs, 1H), 4.24 (bs, 1H), 4.15-4.05 (m, 1H), 3.65-3.60(m, 2H), 3.60-3.53 (m, 2H), 3.29 (dd, J=14.6, 3.0 Hz, 1H), 3.19-3.12 (m,2H), 3.08 (dd, J=14.6, 7.4 Hz, 1H), 2.99-2.92 (m, 2H), 1.26 (d, J=6.2Hz, 3H).

Example 357:[2-(2-Methyl-tetrahydro-furan-3-ylsulfanyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

The title compound was isolated as a mixture of isomers. MS (ESI): masscalcd. for C₂₆H₂₅F₆N₅OS, 569.17; m/z found, 570 [M+H]⁺. ¹H NMR (CDCl₃):8.38 (dd, J=4.6, 1.3 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.65 (d,J=8.6 Hz, 2H), 7.54 (d, J=8.7 Hz, 2H), 6.97 (dd, J=7.4, 4.8 Hz, 1H),6.63 (bs, 1H), 4.35-4.23 (m, 2H), 4.06-3.98 (m, 1H), 3.82-3.74 (m, 1H),3.68-3.61 (m, 2H), 3.61-3.54 (m, 2H), 3.20-3.14 (m, 2H), 2.98-2.92 (m,2H), 2.55-2.43 (m, 1H), 2.11-2.02 (m, 1H), 1.27 (d, J=6.1 Hz, 3H).

Example 358:[2-(2-Methyl-tetrahydro-furan-3-ylsulfanyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine

The title compound was isolated as a mixture of isomers. MS (ESI): masscalcd. for C₂₆H₂₅F₆N₅OS, 569.17; m/z found, 570 [M+H]⁺. ¹H NMR (CDCl₃):8.39 (dd, J=4.6, 1.4 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H), 7.64 (d,J=8.7 Hz, 2H), 7.59 (d, J=8.7 Hz, 2H), 6.97 (dd, J=7.2, 4.8 Hz, 1H),6.63 (bs, 1H), 4.00-3.92 (m, 1H), 3.90-3.81 (m, 2H), 3.81-3.74 (m, 1H),3.67-3.60 (m, 2H), 3.60-3.53 (m, 2H), 3.31-3.25 (m, 2H), 2.99-2.92 (m,2H), 2.59-2.46 (m, 1H), 2.04-1.93 (m, 1H), 1.30 (d, J=6.0 Hz, 3H).

Example 359:2-[(Phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₂₃F₆N₅O₂S₂, 639.12; m/z found, 640 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.91-7.85 (m, 3H),7.79-7.74 (m, 2H), 7.42-7.37 (m, 2H), 7.33-7.26 (m, 2H), 7.26-7.22 (m,1H), 6.98 (dd, J=8.2, 5.2 Hz, 1H), 6.86 (bs, 1H), 4.40 (s, 2H),3.65-3.55 (m, 4H), 3.25-3.20 (m, 2H), 3.01-2.96 (m, 2H).

Example 360:2-(Cyclohexylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₇H₂₇F₆N₅O₂S₂, 631.15; m/z found, 632 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.8, 1.6 Hz, 1H), 7.97 (d, J=8.9 Hz, 2H),7.90-7.84 (m, 3H), 6.98 (dd, J=7.6, 4.7 Hz, 1H), 6.88 (bs, 1H),3.75-3.67 (m, 1H), 3.64-3.60 (m, 2H), 3.60-3.54 (m, 2H), 3.21-3.15 (m,2H), 3.02-2.95 (m, 2H), 2.16-2.07 (m, 2H), 1.85-1.74 (m, 2H), 1.69-1.61(m, 1H), 1.57-1.45 (m, 2H), 1.45-1.25 (m, 3H).

Example 361:2-[(1-Methylethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅O₂S₂, 591.12; m/z found, 592 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.96 (d, J=8.9 Hz, 2H),7.90-7.84 (m, 3H), 6.98 (dd, J=7.4, 4.8 Hz, 1H), 6.90 (bs, 1H), 3.90(sept, J=6.8 Hz, 1H), 3.66-3.60 (m, 2H), 3.60-3.54 (m, 2H), 3.23-3.18(m, 2H), 3.03-2.95 (m, 2H), 1.43 (d, J=6.8 Hz, 3H).

Example 362:1-({7-[3-(Trifluoromethyl)pyridin-2-yl]-4-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}sulfanyl)propan-2-ol

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅O₃S₂, 607.11; m/z found, 608 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.7, 1.6 Hz, 1H), 8.01-7.95 (m, 2H),7.91-7.84 (m, 3H), 7.02-6.94 (m, 2H), 4.19 (bs, 1H), 4.19-4.10 (m, 1H),3.65-3.58 (m, 2H), 3.58-3.52 (m, 2H), 3.33 (dd, J=14.6, 3.1 Hz, 1H),3.21-3.13 (m, 2H), 3.15 (dd, J=14.6, 7.2 Hz, 1H), 3.03, 2.95 (m, 2H),1.30 (d, J=6.2 Hz, 3H).

Example 363:[2-(2-Methyl-tetrahydro-furan-3-ylsulfanyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine

The title compound was prepared using 2-methyltetrahydrofuran-3-thiol,obtained as a mixture of isomers from Acros Organics (cat. #33270 0010).Upon purification by reverse phase HPLC (Phenomenex Gemini 5 μm C₁₈column, 30×100 mm, gradient of acetonitrile in 20 mM aqueous NH₄OH), thetitle compound was isolated as a single diastereomer of unknownstereochemistry. Analytical HPLC: Waters Xterra MS C₁₈ 5 μm column,4.6×100 mm, gradient over 7 min from 1 to 99% acetonitrile in watermodified with 0.05% TFA, 1.0 mL/min; t_(R)=8.07 min. MS (ESI): masscalcd. for C₂₆H₂₅F₆N₅O₃S₂, 633.13; m/z found, 634 [M+H]⁺. ¹H NMR(CDCl₃): 8.38 (dd, J=4.6, 1.5 Hz, 1H), 7.97 (d, J=8.9 Hz, 2H), 7.89 (dd,J=7.8, 1.8 Hz, 1H), 7.85 (d, J=9.0 Hz, 2H), 6.98 (dd, J=8.1, 5.4 Hz,1H), 6.89 (bs, 1H), 4.03-3.96 (m, 1H), 3.93-3.84 (m, 2H), 3.84-3.78 (m,1H), 3.66-3.61 (m, 2H), 3.23-3.18 (m, 2H), 3.03-2.95 (m, 2H), 2.61-2.50(m, 1H), 2.06-1.95 (m, 1H), 1.33 (d, J=6.0 Hz, 3H).

Example 364:N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-[(phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₂₅F₆N₅S, 589.17; m/z found, 590 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.86 (d, J=8.3 Hz, 1H), 7.48-7.45 (m, 1H), 7.42-7.37 (m, 1H), 7.26-7.16(m, 5H), 6.96 (dd, J=7.7, 4.8 Hz, 1H), 6.35 (bs, 1H), 4.25 (s, 2H),3.68-3.61 (m, 2H), 3.61-3.54 (m, 2H), 3.21-3.15 (m, 2H), 2.97-2.91 (m,2H), 2.31 (s, 3H).

Example 365:2-(Cyclohexylsulfanyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₈H₂₉F₆N₅S, 581.20; m/z found, 582 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.8, 1.6 Hz, 1H), 7.98 (d, J=9.0 Hz, 1H), 7.87(dd, J=7.8, 1.8 Hz, 1H), 7.49-7.44 (m, 2H), 6.96 (dd, J=7.6, 4.7 Hz,1H), 6.37 (bs, 1H), 3.68-3.61 (m, 2H), 3.61-3.45 (m, 3H), 3.19-3.12 (m,2H), 2.98-2.92 (m, 2H), 2.34 (s, 3H), 2.05-1.95 (m, 2H), 1.77-1.65 (m,2H), 1.65-1.53 (m, 1H), 1.48-1.34 (m, 2H), 1.33-1.17 (m, 3H).

Example 366:2-[(1-Methylethyl)sulfanyl]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₅S, 541.17; m/z found, 542 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.88(dd, J=7.8, 1.8 Hz, 1H), 7.49-7.43 (m, 2H), 6.96 (dd, J=7.8, 5.1 Hz,1H), 6.38 (bs, 1H), 3.74 (sept, J=6.8 Hz, 1H), 3.69-3.62 (m, 2H),3.62-3.55 (m, 2H), 3.21-3.14 (m, 2H), 2.98-2.91 (m, 2H), 2.35 (s, 3H),1.34 (d, J=6.8 Hz, 6H).

Example 367:1-[(4-{[2-Methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)sulfanyl]propan-2-ol

MS (ESI): mass calcd. for C₂₅H₂₅F₆N₅OS, 557.17; m/z found, 558 [M+H]⁺.¹H NMR (CDCl₃): 8.39 (dd, J=4.7, 1.5 Hz, 1H), 7.88 (dd, J=7.7, 1.8 Hz,1H), 7.86 (d, J=8.6 Hz, 1H), 7.53-7.47 (m, 2H), 6.97 (dd, J=7.6, 4.8 Hz,1H), 6.39 (bs, 1H), 4.02-3.93 (m, 1H), 3.67-3.61 (m, 2H), 3.61-3.53 (m,2H), 3.22-3.13 (m, 3H), 2.33 (s, 3H), 1.17 (d, J=6.2 Hz, 3H).

Example 368:2,5-Anhydro-1,4-dideoxy-3-S-(4-{[2-methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-3-thiopentitol

The title compound was isolated as a mixture of isomers. MS (ESI): masscalcd. for C₂₇H₂₇F₆N₅OS, 583.18; m/z found, 584 [M+H]⁺. ¹H NMR (CDCl₃):8.41-8.37 (m, 1H), 7.91-7.85 (m, 2H), 7.48 (s, 2H), 6.97 (dd, J=7.8, 4.8Hz, 1H), 6.37 (bs, 1H), 4.20-4.15 (m, 1H), 3.92-3.83 (m, 1H), 3.83-3.76(m, 2H), 3.68-3.55 (m, 4H), 3.20-3.14 (m, 2H), 2.99-2.92 (m, 2H),2.42-2.32 (m, 1H), 2.34 (s, 3H), 1.96-1.88 (m, 1H), 1.23 (d, J=6.1 Hz,3H).

Example 369:2,5-Anhydro-1,4-dideoxy-3-S-(4-{[2-methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-3-thiopentitol

The title compound was isolated as a mixture of isomers. MS (ESI): masscalcd. for C₂₇H₂₇F₆N₅OS, 583.18; m/z found, 584 [M+H]⁺. ¹H NMR (CDCl₃):8.39 (dd, J=4.8, 1.5 Hz, 1H), 7.92-7.85 (m, 2H), 7.50-7.45 (m, 2H), 6.97(dd, J=7.4, 4.8 Hz, 1H), 6.37 (bs, 1H), 3.92-3.83 (m, 1H), 3.85-3.76 (m,2H), 3.68-3.55 (m, 5H), 3.21-3.15 (m, 2H), 3.00-2.93 (m, 2H), 2.42-2.32(m, 1H), 2.34 (s, 3H), 1.96-1.87 (m, 1H), 1.23 (d, J=6.1 Hz, 3H).

Example 370:2-[(Phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₃H₃₅F₃N₆S, 604.26; m/z found, 605 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.29-7.14 (m, 5H), 7.11 (d, J=8.0 Hz, 1H), 6.94 (dd, J=7.4, 4.5 Hz, 1H),6.77-6.71 (m, 2H), 6.37 (bs, 1H), 4.33 (s, 2H), 3.68-3.54 (m, 4H),3.27-3.19 (m, 2H), 3.19-3.11 (m, 2H), 2.93-2.84 (m, 2H), 2.89 (s, 3H),1.78-1.71 (m, 2H), 1.26 (s, 6H).

Example 371:2-(Cyclohexylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₃₂H₃₉F₃N₆S, 596.29; m/z found, 597 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.7, 1.5 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz, 1H),7.13 (d, J=8.2 Hz, 1H), 6.93 (dd, J=7.6, 4.6 Hz, 1H), 6.88 (dd, J=8.2,2.0 Hz, 1H), 6.51 (d, J=2.0 Hz, 1H), 6.33 (bs, 1H), 3.69-3.59 (m, 3H),3.59-3.53 (m, 2H), 3.26-3.21 (m, 2H), 3.17-3.10 (m, 2H), 2.92-2.84 (m,2H), 2.90 (s, 3H), 2.09-2.01 (m, 2H), 1.79-1.65 (m, 4H), 1.62-1.53 (m,1H), 1.48-1.37 (m, 2H), 1.37-1.15 (m, 3H), 1.28 (s, 6H).

Example 372:2-[(1-Methylethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₉H₃₅F₃N₆S, 556.26; m/z found, 557 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 7.86 (dd, J=7.8, 1.9 Hz, 1H),7.11 (d, J=8.2 Hz, 1H), 6.96-6.90 (m, 1H), 6.87-6.82 (m, 1H), 6.69-6.65(m, 1H), 6.37 (bs, 1H), 3.95-3.85 (m, 1H), 3.65-3.60 (m, 2H), 3.60-3.54(m, 2H), 3.26-3.20 (m, 2H), 3.17-3.10 (m, 2H), 2.93-2.85 (m, 5H),1.79-1.74 (m, 2H), 1.37 (d, J=6.8 Hz, 6H), 1.28 (s, 6H).

Example 373:1-({7-[3-(Trifluoromethyl)pyridin-2-yl]-4-[(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}sulfanyl)propan-2-ol

MS (ESI): mass calcd. for C₂₉H₃₅F₃N₆OS, 572.25; m/z found, 573 [M+H]⁺.¹H NMR (CDCl₃): 8.38 (dd, J=4.6, 1.4 Hz, 1H), 7.86 (dd, J=7.8, 1.8 Hz,1H), 7.14 (d, J=8.2 Hz, 1H), 6.95 (dd, J=7.7, 4.8 Hz, 1H), 6.75 (d,J=2.1 Hz, 1H), 6.68 (dd, J=8.2, 2.2 Hz, 1H), 6.40 (bs, 1H), 4.33 (bs,1H), 4.07-3.99 (m, 1H), 3.66-3.60 (m, 2H), 3.60-3.52 (m, 2H), 3.27-3.21(m, 2H), 3.20-3.10 (m, 3H), 3.05 (dd, J=14.5, 7.0 Hz, 1H), 2.92 (s, 3H),2.91-2.84 (m, 2H), 1.78-1.71 (m, 2H), 1.27 (s, 6H), 1.20 (d, J=6.2 Hz,3H).

Example 374:2,5-Anhydro-1,4-dideoxy-3-thio-3-S-{7-[3-(trifluoromethyl)pyridin-2-yl]-4-[(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}pentitol

The title compound was isolated as a mixture of isomers. MS (ESI): masscalcd. for C₃₁H₃₇F₃N₆OS, 598.27; m/z found, 599 [M+H]⁺. ¹H NMR (CDCl₃):8.38 (dd, J=4.6, 1.7 Hz, 12H), 7.86 (dd, J=7.7, 1.8 Hz, 1H), 7.12 (d,J=8.2 Hz, 1H), 6.94 (dd, J=7.8, 4.2 Hz, 1H), 6.75 (dd, J=8.2, 2.2 Hz,1H), 6.64 (d, J=2.1 Hz, 1H), 6.36 (bs, 1H), 3.93-3.80 (m, 3H), 3.78-3.71(m, 1H), 3.66-3.61 (m, 2H), 3.61-3.54 (m, 2H), 3.24 (t, J=5.9 Hz, 2H),3.17-3.11 (m, 2H), 2.93-2.87 (m, 2H), 2.91 (s, 3H), 2.52-2.42 (m, 1H),2.00-1.90 (m, 1H), 1.76 (t, J=5.9 Hz, 2H), 1.27 (s, 6H), 1.24 (d, J=6.1Hz, 3H).

Example 375:2-(Propylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS (ESI): mass calcd. for C₂₄H₂₃F₆N₅S, 527.16; m/z found, 528 [M+H]⁺. ¹HNMR (CDCl₃): 8.38 (dd, J=4.7, 1.4 Hz, 1H), 7.88 (dd, J=7.8, 1.8 Hz, 1H),7.67 (d, J=8.6 Hz, 2H), 7.58 (d, J=8.6 Hz, 2H), 6.96 (dd, J=7.2, 4.8 Hz,1H), 6.62 (bs, 1H), 3.66-3.61 (m, 2H), 3.61-3.54 (m, 2H), 3.20-3.13 (m,2H), 3.08-3.02 (m, 2H), 2.98-2.91 (m, 2H), 1.73 (sextet, J=7.4 Hz, 2H),1.00 (t, J=7.3 Hz, 3H).

The compounds in Examples 376-394 were prepared using methods analogousto those described in the preceding examples.

Example 376:2-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionicacid methyl ester

MS: mass calcd. for C₂₉H₃₃F₃N₆O₃, 570.2567; m/z found, 571.3 [M+H]⁺. ¹HNMR (CDCl₃): 8.41-8.38 (m, 1H), 7.88 (dd, J=1.8, 7.8 Hz, 1H), 7.53-7.48(m, 2H), 7.33-7.29 (m, 2H), 6.98-6.92 (m, 1H), 6.40 (s, 1H), 3.80-3.72(m, 8H), 3.67 (s, 3H), 3.64-3.56 (m, 4H), 3.11-3.06 (m, 2H), 2.89-2.85(m, 2H), 1.60 (s, 6H).

Example 377:2-(1-Methylethyl)-N-(4-pyrrolidin-1-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS: mass calcd. for C₂₇H₃₁F₃N₆, 496.2562; m/z found, 497.3 [M+H]⁺. ¹HNMR (CDCl₃): 8.41-8.38 (m, 1H), 7.88 (dd, J=1.8, 7.8 Hz, 1H), 7.47-7.43(m, 2H), 6.97-6.92 (m, 1H), 6.60-6.55 (m, 2H), 6.31 (s, 1H), 3.69-3.59(m, 4H), 3.34-3.28 (m, 4H), 3.22-3.17 (m, 2H), 3.02-2.94 (m, 1H),2.93-2.87 (m, 2H), 2.07-1.98 (m, 4H), 1.30 (d, J=6.9 Hz, 6H).

Example 378:2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine

MS: mass calcd. for C₂₆H₂₆F₆N₆O₂S, 600.1742; m/z found, 601.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.42-8.38 (m, 1H), 7.97-7.93 (m, 2H), 7.89 (dd, J=1.8, 7.8Hz, 1H), 7.86-7.82 (m, 2H), 6.99-6.95 (m, 1H), 6.78 (s, 1H), 3.81-3.72(m, 4H), 3.63-3.52 (m, 4H), 3.14-3.09 (m, 2H), 2.94-2.88 (m, 2H),1.74-1.60 (m, 6H).

Example 379:N,N-Dimethyl-4-({2-morpholin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzenesulfonamide

MS: mass calcd. for C₂₆H₃₀F₃N₇O₃S, 577.2083; m/z found, 578.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.42-8.39 (m, 1H), 7.89 (dd, J=1.8, 7.8 Hz, 1H), 7.79-7.67(m, 4H), 7.00-6.95 (m, 1H), 6.64 (s, 1H), 3.82-3.73 (m, 8H), 3.64-3.55(m, 4H), 3.15-3.09 (m, 2H), 2.95-2.88 (m, 2H), 2.73 (s, 6H).

Example 380:1-[4-({2-Morpholin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanone

MS: mass calcd. for C₂₆H₂₇F₃N₆O₂, 512.2148; m/z found, 513.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.42-8.39 (m, 1H), 7.99-7.94 (m, 2H), 7.89 (dd, J=1.8, 7.8Hz, 1H), 7.66-7.60 (m, 2H), 6.99-6.94 (m, 1H), 6.63 (s, 1H), 3.82-3.74(m, 8H), 3.64-3.55 (m, 4H), 3.14-3.09 (m, 2H), 2.93-2.89 (m, 2H), 2.60(s, 3H).

Example 381:(3-Chloro-4-trifluoromethyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS: mass calcd. for C₂₅H₂₃ClF₆N₆O, 572.1526; m/z found, 573.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.42-8.39 (m, 1H), 8.00 (d, J=2.0 Hz, 1H), 7.89 (dd, J=1.8,7.8 Hz, 1H), 7.61 (d, J=8.6 Hz, 1H), 7.38-7.35 (m, 1H), 7.00-6.95 (m,1H), 6.55 (s, 1H), 3.83-3.74 (m, 8H), 3.63-3.55 (m, 4H), 3.14-3.08 (m,2H), 2.92-2.87 (m, 2H).

Example 382:2-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionitrile

MS: mass calcd. for C₂₈H₃₀F₃N₇O, 537.2464; m/z found, 538.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.40-8.36 (m, 1H), 7.87 (dd, J=1.8, 7.8 Hz, 1H), 7.58-7.52(m, 2H), 7.44-7.39 (m, 2H), 6.97-6.90 (m, 1H), 6.42 (s, 1H), 3.81-3.69(m, 8H), 3.64-3.53 (m, 4H), 3.11-3.05 (m, 2H), 2.90-2.84 (m, 2H), 1.73(s, 6H).

Example 383:2-Methyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-1-ol

MS: mass calcd. for C₂₉H₃₅F₃N₆O, 540.2825; m/z found, 541.3 [M+H]⁺. ¹HNMR (CDCl₃): 8.43-8.36 (m, 1H), 7.87 (dd, J=1.8, 7.8 Hz, 1H), 7.58-7.53(m, 2H), 7.36-7.32 (m, 2H), 6.96-6.91 (m, 1H), 6.35 (s, 1H), 3.78-3.72(m, 4H), 3.65-3.56 (m, 6H), 3.11-3.05 (m, 2H), 2.89-2.83 (m, 2H),1.71-1.58 (m, 6H), 1.36 (s, 6H).

Example 384:2-Methyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionitrile

MS: mass calcd. for C₂₉H₃₂F₃N₇, 535.2672; m/z found, 536.3 [M+H]⁺. ¹HNMR (CDCl₃): 8.42-8.36 (m, 1H), 7.88 (dd, J=1.8, 7.8 Hz, 1H), 7.62-7.57(m, 2H), 7.44-7.40 (m, 2H), 6.96-6.92 (m, 1H), 6.40 (s, 1H), 3.78-3.72(m, 4H), 3.65-3.54 (m, 4H), 3.11-3.06 (m, 2H), 2.89-2.84 (m, 2H), 1.75(s, 6H), 1.71-1.58 (m, 6H).

Example 385:2-Fluoro-4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester

MS: mass calcd. for C₂₇H₂₈F₄N₆O₂, 544.221; m/z found, 545.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.43-8.37 (m, 1H), 7.93-7.86 (m, 2H), 7.75 (dd, J=2.1, 14.0Hz, 1H), 7.14 (dd, J=2.1, 8.7 Hz, 1H), 6.98-6.94 (m, 1H), 6.60 (s, 1H),3.93 (s, 3H), 3.79-3.75 (m, 4H), 3.61-3.55 (m, 4H), 3.13-3.06 (m, 2H),2.90-2.85 (m, 2H), 1.73-1.59 (m, 6H).

Example 386:(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS: mass calcd. for C₂₆H₂₇F₆N₇O, 567.2181; m/z found, 568.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.43-8.39 (m, 1H), 7.93-7.87 (m, 2H), 7.83 (d, J=8.5 Hz,1H), 7.16 (s, 1H), 6.98-6.94 (m, 1H), 4.00 (s, 3H), 3.81-3.75 (m, 4H),3.65-3.55 (m, 4H), 3.14-3.09 (m, 2H), 2.96-2.92 (m, 2H), 1.73-1.60 (m,6H).

Example 387:4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester

MS: mass calcd. for C₂₇H₂₉F₃N₆O₂, 526.2304; m/z found, 527.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.41-8.39 (m, 1H), 8.04-7.99 (m, 2H), 7.88 (dd, J=1.8, 7.8Hz, 1H), 7.67-7.60 (m, 2H), 6.97-6.92 (m, 1H), 6.56 (s, 1H), 3.92 (s,3H), 3.79-3.73 (m, 4H), 3.63-3.55 (m, 4H), 3.12-3.07 (m, 2H), 2.91-2.86(m, 2H), 1.71-1.58 (m, 6H).

Example 388:4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid

MS: mass calcd. for C₂₆H₂₇F₃N₆O₂, 512.2148; m/z found, 513.2 [M+H]⁺. ¹HNMR (CD₃OD): 8.47-8.42 (m, 1H), 8.03-8.00 (m, 1H), 7.93-7.88 (m, 2H),7.62-7.58 (m, 2H), 7.14-7.09 (m, 1H), 3.76-3.69 (m, 4H), 3.49-3.44 (m,4H), 3.07-3.03 (m, 2H), 3.02-2.97 (m, 2H), 1.72-1.65 (m, 2H), 1.63-1.55(m, 4H).

Example 389:2-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol

MS: mass calcd. for C₂₇H₃₁F₃N₆O₂, 528.246; m/z found, 529.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.42-8.38 (m, 1H), 7.88 (dd, J=1.8, 7.8 Hz, 1H), 7.53-7.49(m, 2H), 7.48-7.44 (m, 2H), 6.97-6.93 (m, 1H), 6.40 (s, 1H), 3.82-3.72(m, 8H), 3.67-3.56 (m, 4H), 3.12-3.07 (m, 2H), 2.90-2.86 (m, 2H), 1.62(s, 6H).

Example 390:(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine

MS: mass calcd. for C₂₅H₂₄ClF₆N₇, 571.1686; m/z found, 572.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.44-8.39 (m, 1H), 8.34 (d, J=8.7 Hz, 1H), 7.95 (d, J=8.7Hz, 1H), 7.89 (dd, J=1.8, 7.8 Hz, 1H), 7.43 (s, 1H), 7.00-6.95 (m, 1H),3.81-3.73 (m, 4H), 3.57-3.52 (m, 4H), 3.13-3.09 (m, 2H), 2.94-2.90 (m,2H), 1.74-1.59 (m, 6H).

Example 391:2-{2-Fluoro-4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol

MS: mass calcd. for C₂₈H₃₂F₄N₆O, 544.2574; m/z found, 545.3 [M+H]⁺. ¹HNMR (CDCl₃): 8.41-8.35 (m, 1H), 7.86 (dd, J=1.8, 7.8 Hz, 1H), 7.61 (dd,J=2.2, 14.9 Hz, 1H), 7.45-7.40 (m, 1H), 7.08 (dd, J=2.2, 8.5 Hz, 1H),6.95-6.90 (m, 1H), 6.38 (s, 1H), 3.78-3.71 (m, 4H), 3.62-3.53 (m, 4H),3.10-3.03 (m, 2H), 2.87-2.80 (m, 2H), 2.09 (d, J=3.5 Hz, 1H), 1.69-1.57(m, 12H).

Example 392:2-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionicacid

MS: mass calcd. for C₂₈H₃₁F₃N₆O₃, 556.241; m/z found, 557.2 [M+H]⁺. ¹HNMR (CDCl₃): 8.46-8.42 (m, 1H), 8.02 (dd, J=1.8, 7.8 Hz, 1H), 7.55-7.51(m, 2H), 7.35-7.32 (m, 2H), 7.13-7.10 (m, 1H), 3.76-3.65 (m, 8H),3.49-3.44 (m, 4H), 3.08-3.03 (m, 2H), 3.01-2.97 (m, 2H), 1.55 (s, 6H).

Example 393:5-Chloro-6-[2-piperidin-1-yl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-nicotinicacid methyl ester

MS: mass calcd. for C₂₇H₂₈ClF₃N₆O₂, 560.1914; m/z found, 561.2 [M+H]⁺.¹H NMR (CDCl₃): 8.77-8.62 (m, 1H), 8.38-7.86 (m, 1H), 7.73-7.63 (m, 2H),7.61-7.55 (m, 1H), 7.35-7.28 (m, 1H), 6.62-6.37 (m, 1H), 4.03-3.79 (m,7H), 3.80-3.70 (m, 4H), 3.21-3.04 (m, 2H), 2.98-2.88 (m, 2H), 1.74-1.61(m, 6H).

Example 394:{5-Chloro-6-[2-piperidin-1-yl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-pyridin-3-yl}-methanol

MS: mass calcd. for C₂₆H₂₈ClF₃N₆O, 532.1965; m/z found, 533.2 [M+H]⁺. ¹HNMR ((CD₃)₂CO): 8.20-8.09 (m, 2H), 7.96-7.88 (m, 2H), 7.71 (d, J=2.0 Hz,1H), 7.61 (d, J=8.7 Hz, 2H), 4.66-4.48 (m, 2H), 3.84-3.69 (m, 4H),3.60-3.47 (m, 4H), 3.13-2.97 (m, 4H), 1.75-1.49 (m, 6H).

The compounds in Examples 395-518 are prepared using methods analogousto those described in the preceding examples.

Example Chemical Name 395N²,N²-Dimethyl-N⁶-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine 3962-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-N-methyl-isobutyramide 397[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine 398(4-Methanesulfonyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 399[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 400[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine4011,1,1-Trifluoro-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol 4022-{2-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol 4032-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-1-ol 404[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 405N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-N²-methyl-3-trifluoromethyl-pyridine-2,6-diamine 4062-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 407N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine 408[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine 4092-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 410(3-Fluoro-4-trifluoromethyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine4111-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidmethyl ester 412[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine 4131-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic aciddimethylamide 414[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 4152-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 416N⁶-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine417 (6-Chloro-5-trifluoromethyl-pyridin-2-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 418[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine 419[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 420(4-Bromo-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 421(4-Chloro-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 422(1-Methyl-1,2,3,4-tetrahydro-quinolin-7-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 423[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine 4242-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionitrile 4254-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid methyl ester 4264-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid 427N²-Methyl-N⁶-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine 4282-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid methyl ester4292-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid 4301-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol 431[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 432N,N-Dimethyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 4331-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidmethyl ester 434(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 4351-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acid436 (1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol 437[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 438[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 4391-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidamide 4401-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidmethylamide 441N-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 442N,N-Dimethyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 443[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 444[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 445N⁶-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine446N²-Methyl-N⁶-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine 447N²,N²-Dimethyl-N⁶-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine 448[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine 449[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine 450[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine 451[4-(Morpholine-4-sulfonyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine452[4-(Piperazine-1-sulfonyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine453N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-N²,N²-dimethyl-3-trifluoromethyl-pyridine-2,6-diamine 454N⁶-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine 455[4-(1-Methylaminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 456N²-Methyl-N⁶-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine 457N²,N²-Dimethyl-N⁶-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine 4581,1,1-Trifluoro-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol 459[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 460[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine 461(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 4622-{2-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol 4632-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid 4642-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acidmethyl ester 465(3-Fluoro-4-trifluoromethyl-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 4662-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 467N-Methyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 468N,N-Dimethyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 4692-{2-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol 4702-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid 4712-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoic acid methyl ester4722-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-N,N-dimethyl-isobutyramide 473N-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide 474(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 475(4-Bromo-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 476[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine 477[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine 478[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine 4791-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidmethylamide 4801-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol 4811-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidamide 482(4-Bromo-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 483(4-Methanesulfonyl-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 484(1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol 485[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine 486[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 487[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 488[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine4892-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-1-ol 4901-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acid 491[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 4921-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acid methylamide 493[4-(1-Methylaminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 494[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 495[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 496[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 4971-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acid dimethylamide 4981-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acid amide 4991-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acid methyl ester 5001-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acid 501[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(pyrrolidine-1-sulfonyl)-phenyl]-amine502(1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol 5031-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol 504[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine 505[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine 506[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine 507[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine508[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(1-methylaminomethyl-cyclopropyl)-phenyl]-amine 509[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine 5101-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic aciddimethylamide 5111-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidamide 512(1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol 5131-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol 5141-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidmethyl ester 515[4-(Morpholine-4-sulfonyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine5161-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acid5171-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic acidmethylamide 5181-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylic aciddimethylamideBiological Testing:Functional Assay: Block of Capsaicin-Induced Ca²⁺ InfluxA. Human Assay

HEK293 cells were transfected with human TRPV1 cloned in pcDNA3.1zeo(+)using the Effectene non-liposomal lipid based transfection kit (Qiagen)(hTRPV1/HEK293). hTRPV1/HEK293 cells were routinely grown as monolayersunder selection in zeocin (200 μg/mL; Invitrogen) in Dulbecco's ModifiedEagle Medium (DMEM, Gibco BRL) supplemented with 10% fetal bovine serum,and penicillin/streptomycin (50 units/mL) in 5% CO₂ at 37° C. Cells werepassaged frequently, every 3-5 days, to avoid overgrowth, depletion ofessential medium components, or acidic medium exposure. Cells werepassaged using a brief wash in 0.05% trypsin with 1 mM EDTA, followed bydissociation in divalent-free phosphate-buffered saline (Hyclone#SH30028.02). Dissociated cells were seeded onto poly-D-lysine coatedblack-walled 96-well plates (Biocoat; Becton Dickinson #354640) at about40,000 cells per well and grown for approximately 1 day in culturemedium to near confluency. The assay buffer was composed of 130 mM NaCl,2 mM KCl, 2 mM MgCl₂, 10 mM HEPES, 5 mM glucose, and either 2 mM or 20μM CaCl₂. On the day of the experiment, the culture medium was replacedwith 2 mM calcium assay buffer using an automated plate washer (ELx405;Biotek, VT). The cells were incubated in 100 μL/well Fluo-3/AM (2 μM;TEFLabs #0116) with Pluronic F127 (100 μg/mL; Sigma #P2443) for 1 h atrt in the dark. After loading the cells, the dye solution was replacedwith 50 μL/well of 20 μM calcium assay buffer using the ELx405 platewasher. Test compounds (50 μL/well) were added to the plate andincubated for 30 min. Intracellular Ca²⁺ levels were subsequentlyassayed using a Fluorometric Imaging Plate Reader (FLIPR™ instrument,Molecular Devices, CA) to simultaneously monitor Fluo-3 fluorescence inall wells (λ_(excitation)=488 nm, λ_(emission)=540 nm) during challengewith agonist (capsaicin). The IC₅₀ values were determined. Cells werechallenged with 150 nM capsaicin and the fluorescence counts werecaptured following agonist addition at a sampling rate of 0.33 Hz. Thecontents of the wells were mixed 3 times (40 μL mix volume) immediatelyafter the additions were made. Concentration dependence of block wasdetermined by exposing each well of cells in duplicate rows of a 96 wellplate to a serial dilution of test compound. The concentration seriesusually started at 10 μM with a three-fold serial decrement inconcentration. The magnitude of the capsaicin response was determined bymeasuring the change in fluo3 fluorescence before and 100 seconds afterthe addition of the agonist. Data were analyzed using a non-linearregression program (Origin; OriginLab, MA). Results for the compoundstested in this assay are presented in Table 1. IC₅₀ values shown are theaverage (mean) of the results obtained.

B. Rat Assay

The assay was performed as described above, using HEK293 cellstransfected with rat TRPV1 (rTRPV1/HEK293). These cells had a geneticinselection marker and were grown in Dulbecco's Modified Eagle Medium(DMEM, Gibco BRL) supplemented with 10% fetal bovine serum,penicillin/streptomycin (50 units/mL), and 500 μg/mL geneticin in 5% CO₂at 37° C. Results for the compounds tested in this assay are alsopresented in Table 1. IC₅₀ values shown are the average (mean) of theresults obtained. Where activity is shown as greater than (>) aparticular value, the value is the solubility limit of the compound inthe assay medium.

TABLE 1 Human Rat Ex. IC₅₀ (μM) IC₅₀ (μM)  1 0.029 0.090  1A 0.016 0.049 2 0.072 0.79  2A 0.075 0.42  3 0.019 0.095  4 0.20 0.50  5 0.060 0.15 5A 0.042 0.19  6 0.0059 0.49  7 0.018 0.14  8 0.018 0.025  9 0.0780.092  9A 0.051 0.052  10 0.63 0.93  11 0.20 0.20  12 0.53 0.95  13 0.461.3  14 0.010 0.040  15 0.082 0.046  16 0.041 0.10  17 0.081 NT 18 >6.7 >6.7  19 0.36 0.51  20 0.050 0.032  20A 0.17 0.25  21 0.82 1.1 22 0.075 0.13  23 0.14 0.31  24 0.18 0.29  25 >6.7 0.77  26 >6.7 >6.7 27 5.2 10  28 >6.7 >6.7  29 0.70 0.34  30 0.51 1.3  31 0.39 0.53  321.74 0.013  33 1.1 0.11  34 1.5 0.36  35 1.5 2.4  36 0.17 0.37  37 0.410.15  38 1.1 1.4  39 0.0060 0.018  39A 0.0095 0.023  40 0.0037 0.056 40A 0.0053 0.019  41 0.038 0.049  42 0.018 0.049  43B 0.061 0.39  440.12 0.25  45 0.042 0.090  46 0.20 0.38  47 0.0068 0.023  48 0.018 0.074 49 0.027 0.24  50B 0.18 0.91  51 0.93 1.2  52 0.028 0.053  53 0.50 >6.7 54 0.15 0.23  55B 0.14 0.15  56B 0.024 0.064  57B 3.3 5.5  58B 0.34 1.5 59B 0.073 0.38  60B 0.031 0.14  61B 0.11 0.23  62 0.037 0.053  63B 0.442.5  64 >6.7 >6.7  65B 0.030 0.65  66B 0.42 0.93  67B 0.090 0.034  68B3.6 3.2  69 0.37 0.50  70B >20 4.4  71B >20 >20  72B 0.064 0.18  73B >206.7  74B >6.7 3.9  75B NT 0.040  76B 0.090 0.091  77B 0.66 0.58  78B0.69 1.8  79B NT 1.3  80B 0.065 0.13  81B NT 0.97  82B NT 2.8  83 0.620.99  84 NT >20  85 >2.2 >6.7  86 0.37 0.85  87 0.84 0.35  88 1.8 0.96 89 >6.7 >6.7  90B NT >6.7  91B NT 0.24  92B 0.16 0.27  93B 0.0089 0.037 94B 0.086 0.19  95B 0.062 0.082  96 0.28 0.34  97 0.55 0.49 98 >6.7 >6.7  99B 3.3 7.2 100 0.022 0.031 101B >2.2 0.99 102 0.046 0.17103 0.37 0.34 104 0.47 0.32 105 14 >20 106 0.0054 0.062 107 >20 >20 1081.9 0.94 109 0.45 0.58 115 >6.67 3.79 116 >20 7.03 117 >20 13.49 1180.65 0.50 119 1.09 1.22 120 >20 12.05 121 >20 >20 122 1.96 0.19 123 1.020.99 124 0.63 0.57 125 0.52 0.61 126 2.06 1.19 127 >20 19.20 128 0.130.15 129 0.58 0.23 130 >20 >20 131 >6.67 NT 132 >6.67 NT 133 0.47 NT134 >6.67 NT 135 0.07 NT 136 0.07 0.11 137 0.09 0.06 138 0.06 0.03 1390.65 0.62 140 0.10 0.19 141 0.42 0.13 142 1.66 2.09 143 0.08 0.13 1440.06 0.24 145 0.08 0.24 146 0.20 0.72 147 0.10 0.11 148 0.48 2.17 1490.02 0.15 150 0.02 0.20 151 2.31 0.82 152 0.62 0.55 153 0.11 0.14 1540.45 1.14 155 0.62 3.28 156 0.06 0.59 157 0.004 0.07 158 0.02 0.06 1590.004 0.03 160 0.02 0.10 161 0.29 0.13 162 0.09 0.03 163 0.08 0.12 1640.03 0.02 165 3.51 2.25 166 0.04 0.38 167 0.06 0.37 168 0.02 0.03 1690.28 1.01 170 0.15 0.06 171 0.10 0.08 172 0.06 0.13 173 0.15 0.21 1740.39 2.01 175 0.06 0.08 176 0.54 0.81 177 0.02 0.09 178 0.09 0.11 1790.23 1.34 180 0.03 >6.67 181 0.70 0.82 182 0.87 0.79 183 2.06 2.37 1841.42 1.95 185 >20 >20 186 0.05 0.14 187 1.60 2.85 188 0.24 1.59 189 1.941.93 190 0.60 1.16 191 0.11 0.26 192 0.02 0.07 193 1.39 2.11 194 0.050.07 195 4.42 4.32 196 0.13 0.10 197 0.13 0.15 198 >20 9.16 199 0.391.36 200 0.03 0.11 201 0.56 0.32 202 2.93 12.42 203 >20 >6.67 204 1.220.56 205 0.17 2.28 206 0.13 0.29 207 0.51 0.77 208 >20 >20 209 >6.673.45 210 0.90 NT 211 >20 11.40 212 0.09 0.22 213 0.15 0.11 214 0.01 0.01215 0.02 0.01 216 0.06 0.05 217 0.20 0.39 218 0.09 0.12 219 2.92 3.38220 0.65 1.52 221 0.28 0.72 222 0.01 0.02 223 0.01 0.03 224 0.01 0.02225 3.43 4.67 226 1.71 1.73 227 >20 >20 228 0.09 0.04 229 0.04 0.06 2302.13 0.94 231 0.07 0.10 232 >6.67 >6.67 233 0.04 0.17 234 0.05 0.08 2350.01 0.01 236 0.01 0.01 237 0.01 0.01 238 0.02 0.04 239 0.03 0.03 2400.01 0.02 241 0.01 0.17 242 0.01 0.09 243 0.31 0.45 244 0.002 0.01 2450.01 0.02 246 0.003 0.05 247 >20 >20 248 0.25 0.53 249 0.12 0.83 2500.05 0.09 251 >6.67 1.98 252 0.47 0.45 253 0.01 0.01 254 0.18 0.10 2554.29 0.70 256 >6.67 >6.67 257 0.04 0.02 258 0.02 NT 259 0.03 0.09 2600.02 0.05 261 0.15 0.34 262 0.56 1.64 263 1.13 1.46 264 0.43 1.30 2650.20 0.39 266 0.12 0.45 267 2.48 1.87 268 0.05 0.15 269 0.13 0.18 2700.38 0.83 271 0.18 0.84 272 0.04 0.20 273 0.57 0.68 274 0.04 0.26 2750.17 0.19 276 0.01 0.04 277 0.02 0.05 278 0.63 0.67 279 0.38 >6.67280 >6.67 >6.67 281 1.78 2.62 282 0.31 0.13 283 2.99 8.52 284 1.67 0.55285 >6.67 >6.67 286 >6.67 >6.67 287 >6.67 >6.67 288 2.99 2.02 289 2.840.29 290 0.41 0.10 291 0.27 0.17 292 0.12 0.05 293 9.34 3.49 294 3.392.94 295 4.66 10.43 296 0.42 0.12 297 0.45 1.08 298 0.45 0.37 299 >6.673.00 300 4.07 2.00 301 3.43 8.97 302 0.84 9.46 303 2.03 >6.67 304 >6.67NT 305 1.78 1.12 306 0.61 1.21 307 0.02 0.03 308 0.34 0.36 309 >6.671.42 310 0.28 0.07 311 5.00 >20 312 0.22 0.45 313 0.83 0.56 314 0.190.16 315 1.54 5.52 316 0.09 1.18 317 0.13 0.61 318 0.003 >6.67 319 0.030.24 320 0.005 0.02 321 0.33 0.18 322 0.16 0.01 323 0.56 0.67 324 0.810.10 325 0.05 0.30 326 0.21 0.60 327 0.26 0.89 328 0.08 0.25 329 1.120.12 330 0.01 0.05 331 0.07 0.50 332 0.01 2.04 333 0.01 0.04 334 0.040.04 335 0.03 0.15 336 0.05 1.64 337 0.02 0.17 338 0.03 0.40 339 0.030.19 340 0.05 0.26 341 0.06 0.15 342 0.18 0.06 343 0.04 0.06 344 >20 >20345 0.08 0.19 346 1.38 >6.67 347 1.86 1.32 348 3.02 3.22 349 0.50 2.35350 0.06 0.03 351 >6.67 0.75 352 1.01 >6.67 353 0.01 0.24 354 0.01 0.25355 0.03 0.06 356 0.11 0.29 357 0.02 0.14 358 0.07 0.07 359 0.63 0.32360 0.65 0.25 361 0.10 1.53 362 0.003 0.19 363 0.01 0.06 364 >6.67 1.18365 1.09 >6.67 366 0.23 0.13 367 1.30 >6.67 368 0.13 0.02 369 0.19 0.01370 NT 2.61 371 2.19 >6.67 372 0.03 0.33 373 0.07 0.18 374 0.19 0.004375 0.07 >6.67 376 0.07 0.11 377 2.69 1.41 378 0.04 0.04 379 0.04 0.07380 0.05 0.23 381 0.01 0.04 382 0.02 0.04 383 0.14 0.16 384 0.02 0.04385 0.13 0.82 386 >6.67 >6.67 387 0.10 0.55 388 NT NT 389 0.05 0.32 3900.01 0.09 391 NT NT 392 0.12 1.54 393 0.05 0.12 394 0.17 0.29 NT = nottested

While the invention has been illustrated by reference to exemplary andpreferred embodiments, it will be understood that the invention isintended not to be limited to the foregoing detailed description, but tobe defined by the appended claims as properly construed under principlesof patent law.

What is claimed is:
 1. A compound selected from the group consisting of:(4-tert-Butyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetra-hydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[2-cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Chloro-phenyl)-[2-cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(4-tert-Butyl-phenyl)-[2-phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(4-tert-Butyl-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(3-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;[2-(4-Fluoro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-(2-Chloro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(3,4-Dichloro-benzyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(5-Trifluoromethyl-pyridin-2-yl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;Isoquinolin-1-yl-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-quinolin-3-yl-amine;[2-Phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;[2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-phenoxy-phenyl)-amine;(4-Trifluoromethyl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(7-Pyrimidin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;(7-Pyrazin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;(7-Quinoxalin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;[7-(3-Chloro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(4-tert-Butyl-phenyl)-[7-(6-chloro-5-methyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[2-isopropyl-7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-methanesulfonyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(4-tert-Butyl-phenyl)-(7-phthalazin-1-yl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl)-amine;(4-tert-Butyl-phenyl)-[7-(5-methyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;N²,N²-Dimethyl-N⁴-(6-trifluoromethyl-pyridin-3-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²,N²-Dimethyl-N⁴-(5-trifluoromethyl-pyridin-2-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;N²-Phenyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Cyclopropyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(2-Piperidin-1-yl-ethyl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(Tetrahydro-pyran-4-yl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[2-Methoxy-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;N⁴-(3,4-Dichloro-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-(4-Methoxy-3-trifluoromethyl-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;2-{4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-2-methyl-propionitrile;(4-tert-Butyl-phenyl)[2-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁴-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-Benzyl-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzenesulfonamide;N²,N²-Dimethyl-N⁴-(4-nitro-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-(3,4-Dichloro-benzyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitrile;N⁴-(4-Dimethylamino-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;(3-Chloro-4-trifluoromethyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁴-(4-Methoxy-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-Indan-2-yl-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[7-(5-Amino-3-methyl-pyridin-2-yl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[7-(2-Amino-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(2-nitro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[7-(3-Amino-pyridin-2-yl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-methyl-5-nitro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-nitro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-phenyl}-methanesulfonamide;N²-(2-Methoxy-ethyl)-N²-methyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Cyclopropylmethyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-ethanone;4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitrile;(3,4-Dichloro-benzyl)-[2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethylsulfanyl-phenyl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-pyrimidin-4-yl-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-pyrimidin-2-yl-amine;[2-(3,4-Dichloro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;and(3,4-Dichloro-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;and pharmaceutically acceptable salts thereof.
 2. A compound selectedfrom the group consisting of:N-{[4-Chloro-3-(trifluoromethyl)phenyl]methyl}-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-{[4-(trifluoromethyl)phenyl]methyl}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(2-Fluorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(2-Bromophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[(2,6-Dichlorophenyl)methyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[(2-Chlorophenyl)methyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[4-(1,1-Dimethylethyl)cyclohexyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(3-Chlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(4-Chlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(2,6-Dichlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-{2-[2-(methyloxy)phenyl]ethyl}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N,N-Dimethyl-4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzamide;N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Methyl-2-[4-(2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanenitrile;4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzoicacid;N-Biphenyl-4-yl-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-(4-Cyclohexylphenyl)-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(4-piperidin-1-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(4-morpholin-4-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-[4-(methylsulfanyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(4-nitrophenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-[4-(1-methylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1,1-Dimethylethyl)-N-[4-(1,1-dimethylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1,1-Dimethylethyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[3-Fluoro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-(2,3-Dihydro-1H-inden-5-yl)-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminehydrochloride acid salt;2-(1-Methylethyl)-N-[4-(1,3-oxazol-5-yl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)-3-nitrophenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Furan-2-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-furan-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Furan-3-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-furan-3-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;Benzo[1,2,5]thiadiazol-5-yl-[2-isopropyl-7-(3-trifluoromethyl-pyridin-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-(2-Thienyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(3-Thienyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(4-methylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(2-Methyl-1,3-thiazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N,N-Dimethyl-4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzenesulfonamide;N-[2-Fluoro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-Pyridin-4-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[4-(1,1-Dimethylethyl)phenyl]-2-pyridin-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-Pyridin-2-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-pyridin-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt; Methyl2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate;2-Pyridin-3-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-[4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol;1,1,1-Trifluoro-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol;2-Methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-1-ol;1-[4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanol;2,2,2-Trifluoro-1-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanol;2-Methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoicacid;4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzoicacid trifluoroacetic acid salt;2-(1-Methylethyl)-N-(5-methylpyrazin-2-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[6-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-methoxy-5-trifluoromethyl-pyridin-2-yl)-aminehydrochloride salt;2-Pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;2-(4-Methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Azepan-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²-[2-(Dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;2-Azetidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-{2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}benzene-1,4-diaminetrifluoroacetic acid salt;4-(1,1-Dimethylethyl)-N1-{2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}benzene-1,3-diamine;7-[5-Amino-3-(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-Chloro-4-(trifluoromethyl)phenyl]-2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfanyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfanyl)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-(methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfonyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-[4-(methylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;Methyl5-chloro-6-[2-(methylsulfonyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylate;N²-[2-(Methyloxy)ethyl]-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-(Furan-2-ylmethyl)-N²-methyl-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;2-Azetidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²,N²-Dimethyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-[2-(Dimethylamino)ethyl]-N²-methyl-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;2-(4-Methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Azepan-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²-[2-(Dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-[3-Chloro-4-(trifluoromethyl)phenyl]-N²-[2-(dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-[(3,4-Dichlorophenyl)methyl]-N²-[2-(dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-Methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N⁴-[3-Chloro-4-(trifluoromethyl)phenyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N⁴-[(3,4-Dichlorophenyl)methyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[(3,4-Dichlorophenyl)methyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²-[2-(Dimethylamino)ethyl]-N⁴-[4-(1,1-dimethylethyl)phenyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;2-Azepan-1-yl-N-[(3,4-dichlorophenyl)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[(3,4-Dichlorophenyl)methyl]-2-(4-methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N⁴-[4-(1,1-Dimethylethyl)phenyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[(2S)-1-(7-[3-(Trifluoromethyl)pyridin-2-yl]-4-{[5-(trifluoromethyl)pyridin-2-yl]amino}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)pyrrolidin-2-yl]methanol;N²-[(3R)-Tetrahydrofuran-3-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-[4-(1,1-Dimethylethyl)phenyl]-N²-[(3R)-tetrahydrofuran-3-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(Tetrahydro-furan-3-yl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-Methyl-N²-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Cyclohexyl-N²-methyl-N⁴-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(Cyclohexylmethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Methyl-N²-(1-methylethyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;2-[2-(1-Methylethyl)pyrrolidin-1-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²-Cyclohexyl-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(2-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-(3-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-(4-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N-{2-[2-(1-Methylethyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridin-3-yl}methanesulfonamide;2-(1-Methylethyl)-7-[3-(methylsulfonyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-[3-(Methylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-(3-Aminopyridin-2-yl)-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-(5-Bromo-3-chloropyridin-2-yl)-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(1-methylethyl)-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;5-Chloro-6-[2-(1-methylethyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylicacid trifluoroacetic acid salt;N-[4-(1,1-Dimethylethyl)phenyl]-2-(1-methylethyl)-7-(3-methyl-5-nitropyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-(1-methylethyl)-7-[5-nitro-3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-7-[5-nitro-3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-7-(5-fluoro-3-methylpyridin-2-yl)-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-carbonitrile;2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-carboxamidetrifluoroacetic acid salt;7-(3-Fluoropyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-7-[3-(ethylsulfonyl)pyridin-2-yl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-[3-(Ethylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide;Methyl5-chloro-6-[2-(methylsulfanyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylate;2-(Methylsulfanyl)-7-[3-(methylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;[7-(3-Ethanesulfonyl-pyridin-2-yl)-2-methylsulfanyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;{5-Chloro-6-[2-(methylsulfanyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridin-3-yl}methanol;2-({[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}oxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylpiperidin-4-yl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(Pyrrolidin-1-ylsulfonyl)phenyl]-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-{[1-(1-Methylethyl)pyrrolidin-3-yl]oxy}-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclopropylethyl)oxy]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclopropylethyl)oxy]-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclopropylethyl)oxy]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexyloxy)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Butyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexyloxy)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-({[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}oxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclopropylethyl)oxy]-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(Pyrrolidin-1-ylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cycloheptyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Tetrahydro-2H-pyran-4-yloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Tetrahydrofuran-3-yloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-(Phenyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-(Butyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-oltrifluoroacetic acid salt;2-(Ethyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-[(Methyloxy)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-Methyl-2-[4-({2-[(methyloxy)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanenitriletrifluoroacetic acid salt;2-(Methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Phenylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(Phenylmethyl)sulfanyl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)sulfanyl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;1-[(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)sulfanyl]propan-2-ol;[2-(2-Methyl-tetrahydro-furan-3-ylsulfanyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;2-[(Phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;1-({7-[3-(Trifluoromethyl)pyridin-2-yl]-4-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}sulfanyl)propan-2-ol;[2-(2-Methyl-tetrahydro-furan-3-ylsulfanyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-[(phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexylsulfanyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)sulfanyl]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;1-[(4-{[2-Methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)sulfanyl]propan-2-ol;2,5-Anhydro-1,4-dideoxy-3-S-(4-{[2-methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-3-thiopentitol;2-[(Phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;1-({7-[3-(Trifluoromethyl)pyridin-2-yl]-4-[(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}sulfanyl)propan-2-ol;2,5-Anhydro-1,4-dideoxy-3-thio-3-S-{7-[3-(trifluoromethyl)pyridin-2-yl]-4-[(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}pentitol;2-(Propylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;and2-(1-Methylethyl)-N-(4-pyrrolidin-1-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;and pharmaceutically acceptable salts thereof.
 3. A compound selectedfrom the group consisting of:N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-pyridin-3-yl}-methanesulfonamide;N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-phenyl}-methanesulfonamide;N²-(2-Dimethylamino-ethyl)-N²-methyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²,N²-Dimethyl-N⁶-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;2-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-N-methyl-isobutyramide;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine;(4-Methanesulfonyl-phenyl)[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;1,1,1-Trifluoro-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;2-{2-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;2-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-1-ol;[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-N²-methyl-3-trifluoromethyl-pyridine-2,6-diamine;2-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;2-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;(3-Fluoro-4-trifluoromethyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methyl ester;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid dimethylamide;[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N⁶-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Bromo-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Chloro-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(1-Methyl-1,2,3,4-tetrahydro-quinolin-7-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine;2-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionitrile;4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid;N²-Methyl-N⁶-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;2-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;2-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol;[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N,N-Dimethyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methyl ester;(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid;(1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol;[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid amide;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methylamide;N-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N,N-Dimethyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁶-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;N²-Methyl-N⁶-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;N²,N²-Dimethyl-N⁶-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine;[4-(Morpholine-4-sulfonyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(Piperazine-1-sulfonyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-N²,N²-dimethyl-3-trifluoromethyl-pyridine-2,6-diamine;N⁶-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;[4-(1-Methylaminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N²-Methyl-N⁶-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;N²,N²-Dimethyl-N⁶-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;1,1,1-Trifluoro-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-{2-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;2-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid;2-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;(3-Fluoro-4-trifluoromethyl-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N-Methyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N,N-Dimethyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;2-{2-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;2-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid;2-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;2-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-N,N-dimethyl-isobutyramide;N-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Bromo-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methylamide;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid amide;(4-Bromo-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-1-ol;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid;[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methylamide;[4-(1-Methylaminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid dimethylamide;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid amide;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methyl ester;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(pyrrolidine-1-sulfonyl)-phenyl]-amine;(1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(1-methylaminomethyl-cyclopropyl)-phenyl]-amine;[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid dimethylamide;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid amide;(1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methyl ester;[4-(Morpholine-4-sulfonyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methylamide; and1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid dimethylamide; and pharmaceutically acceptable salts thereof.
 4. Apharmaceutical composition comprising: (a) a therapeutically effectiveamount of a compound selected from the group consisting of:(4-tert-Butyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Trifluoromethyl-phenyl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetra-hydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[2-cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Chloro-phenyl)-[2-cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(4-tert-Butyl-phenyl)-[2-phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(4-tert-Butyl-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(3-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;[2-(4-Fluoro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-(2-Chloro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(3,4-Dichloro-benzyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[2-methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(5-Trifluoromethyl-pyridin-2-yl)-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;Isoquinolin-1-yl-[7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Cyclopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-quinolin-3-yl-amine;[2-Phenyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;[2-Methyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-phenoxy-phenyl)-amine;(4-Trifluoromethyl-phenyl)-[7-(4-trifluoromethyl-pyrimidin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(7-Pyrimidin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;(7-Pyrazin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;(7-Quinoxalin-2-yl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl)-(4-trifluoromethyl-phenyl)-amine;[7-(3-Chloro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(4-tert-Butyl-phenyl)-[7-(6-chloro-5-methyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[2-isopropyl-7-(3-methyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-quinoxalin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-methanesulfonyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;(4-tert-Butyl-phenyl)-(7-phthalazin-1-yl-6,7,8,9-tetrahydro-5H-pyrimido-[4,5-d]azepin-4-yl)-amine;(4-tert-Butyl-phenyl)-[7-(5-methyl-pyrimidin-4-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;N²,N²-Dimethyl-N⁴-(6-trifluoromethyl-pyridin-3-yl)-7-(3-trifluoromethylpyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²,N²-Dimethyl-N⁴-(5-trifluoromethyl-pyridin-2-yl)-7-(3-trifluoromethylpyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Methanesulfonyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;N²-Phenyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Cyclopropyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(2-Piperidin-1-yl-ethyl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(Tetrahydro-pyran-4-yl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[2-Methoxy-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;N⁴-(3,4-Dichloro-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-(4-Methoxy-3-trifluoromethyl-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;2-{4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-2-methyl-propionitrile;(4-tert-Butyl-phenyl)[2-piperidin-1-ylmethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-tert-Butyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁴-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-Benzyl-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzenesulfonamide;N²,N²-Dimethyl-N⁴-(4-nitro-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-(3,4-Dichloro-benzyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyridin-2-yl)-amine;[2-Methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;[2-Methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;4-[2-Dimethylamino-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitrile;N⁴-(4-Dimethylamino-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;(3-Chloro-4-trifluoromethyl-phenyl)-[2-methoxymethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁴-(4-Methoxy-phenyl)-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-Indan-2-yl-N²,N²-dimethyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[7-(5-Amino-3-methyl-pyridin-2-yl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[7-(2-Amino-phenyl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(2-nitro-phenyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[7-(3-Amino-pyridin-2-yl)-2-isopropyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-methyl-5-nitro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;[2-Isopropyl-7-(3-nitro-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-phenyl}-methanesulfonamide;N²-(2-Methoxy-ethyl)-N²-methyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Cyclopropylmethyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-ethanone;4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzonitrile;(3,4-Dichloro-benzyl)-[2-methylsulfanyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethylsulfanyl-phenyl)-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-pyrimidin-4-yl-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-pyrimidin-2-yl-amine;[2-(3,4-Dichloro-phenyl)-ethyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(3,4-Dichloro-phenyl)-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N-[4-Chloro-3-(trifluoromethyl)phenyl]methyl-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-{[4-(trifluoromethyl)phenyl]methyl}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(2-Fluorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(2-Bromophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[(2,6-Dichlorophenyl)methyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[(2-Chlorophenyl)methyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[4-(1,1-Dimethylethyl)cyclohexyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(3-Chlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(4-Chlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-(2,6-Dichlorophenyl)ethyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-{2-[2-(methyloxy)phenyl]ethyl}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N,N-Dimethyl-4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzamide;N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanenitrile;4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzoicacid;N-Biphenyl-4-yl-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-(4-Cyclohexylphenyl)-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(4-piperidin-1-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(4-morpholin-4-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-[4-(methylsulfanyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(4-nitrophenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-[4-(1-methylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1,1-Dimethylethyl)-N-[4-(1,1-dimethylethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1,1-Dimethylethyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[3-Fluoro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-(2,3-Dihydro-1H-inden-5-yl)-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminehydrochloride acid salt;2-(1-Methylethyl)-N-[4-(1,3-oxazol-5-yl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)-3-nitrophenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Furan-2-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-furan-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Furan-3-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-furan-3-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;Benzo[1,2,5]thiadiazol-5-yl-[2-isopropyl-7-(3-trifluoromethyl-pyridin-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-(2-Thienyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(3-Thienyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(4-methylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(2-Methyl-1,3-thiazol-4-yl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N,N-Dimethyl-4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzenesulfonamide;N-[2-Fluoro-4-(trifluoromethyl)phenyl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-Pyridin-4-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[4-(1,1-Dimethylethyl)phenyl]-2-pyridin-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-Pyridin-2-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[3-Chloro-4-(trifluoromethyl)phenyl]-2-pyridin-2-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt; Methyl2-methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoate;2-Pyridin-3-yl-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-[4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol;1,1,1-Trifluoro-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-2-ol;2-Methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propan-1-ol;1-[4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanol;2,2,2-Trifluoro-1-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]ethanol;2-Methyl-2-[4-({2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanoicacid;4-({2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)benzoicacid trifluoroacetic acid salt;2-(1-Methylethyl)-N-(5-methylpyrazin-2-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[6-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-methoxy-5-trifluoromethyl-pyridin-2-yl)-aminehydrochloride salt;2-Pyridin-4-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;2-(4-Methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Azepan-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²-[2-(Dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;2-Azetidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-{2-(1-Methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}benzene-1,4-diaminetrifluoroacetic acid salt;4-(1,1-Dimethylethyl)-N1-{2-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}benzene-1,3-diamine;7-[5-Amino-3-(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-Chloro-4-(trifluoromethyl)phenyl]-2-(methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfanyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfanyl)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-(methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Methylsulfonyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-N-[4-(methylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;Methyl5-chloro-6-[2-(methylsulfonyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylate;N²-[2-(Methyloxy)ethyl]-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-(Furan-2-ylmethyl)-N²-methyl-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;2-Azetidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²,N²-Dimethyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-{[6-(trifluoromethyl)pyridin-3-yl]methyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-[2-(Dimethylamino)ethyl]-N²-methyl-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;2-(4-Methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-Azepan-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²-[2-(Dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-[3-Chloro-4-(trifluoromethyl)phenyl]-N²-[2-(dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-[(3,4-Dichlorophenyl)methyl]-N²-[2-(dimethylamino)ethyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-Methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N⁴-[3-Chloro-4-(trifluoromethyl)phenyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N⁴-[(3,4-Dichlorophenyl)methyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;2-Piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;N-[(3,4-Dichlorophenyl)methyl]-2-piperidin-1-yl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²-[2-(Dimethylamino)ethyl]-N⁴-[4-(1,1-dimethylethyl)phenyl]-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;2-Azepan-1-yl-N-[(3,4-dichlorophenyl)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[(3,4-Dichlorophenyl)methyl]-2-(4-methylpiperazin-1-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N⁴-[4-(1,1-Dimethylethyl)phenyl]-N²-methyl-N²-[2-(methyloxy)ethyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;[(2S)-1-(7-[3-(Trifluoromethyl)pyridin-2-yl]-4-{[5-(trifluoromethyl)pyridin-2-yl]amino}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)pyrrolidin-2-yl]methanol;N²-[(3R)-Tetrahydrofuran-3-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N⁴-[4-(1,1-Dimethylethyl)phenyl]-N²-[(3R)-tetrahydrofuran-3-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(Tetrahydro-furan-3-yl)-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-Methyl-N²-(1-methylethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Cyclohexyl-N²-methyl-N⁴-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(Cyclohexylmethyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-Methyl-N²-(1-methylethyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;2-[2-(1-Methylethyl)pyrrolidin-1-yl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N²-Cyclohexyl-N²-methyl-7-[3-(trifluoromethyl)pyridin-2-yl]-N⁴-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²-(2-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-(3-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N²-(4-Methylphenyl)-N⁴-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diaminetrifluoroacetic acid salt;N-{2-[2-(1-Methylethyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridin-3-yl}methanesulfonamide;2-(1-Methylethyl)-7-[3-(methylsulfonyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-[3-(Methylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-(3-Aminopyridin-2-yl)-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-(5-Bromo-3-chloropyridin-2-yl)-N-[4-(1,1-dimethylethyl)phenyl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-[3-Chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(1-methylethyl)-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;5-Chloro-6-[2-(1-methylethyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylicacid trifluoroacetic acid salt;N-[4-(1,1-Dimethylethyl)phenyl]-2-(1-methylethyl)-7-(3-methyl-5-nitropyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-2-(1-methylethyl)-7-[5-nitro-3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(1-Methylethyl)-7-[5-nitro-3-(trifluoromethyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-7-(5-fluoro-3-methylpyridin-2-yl)-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-carbonitrile;2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-carboxamidetrifluoroacetic acid salt;7-(3-Fluoropyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(1,1-Dimethylethyl)phenyl]-7-[3-(ethylsulfonyl)pyridin-2-yl]-2-(1-methylethyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;7-[3-(Ethylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(4-{[4-(Trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl)pyridine-3-sulfonamide;Methyl5-chloro-6-[2-(methylsulfanyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridine-3-carboxylate;2-(Methylsulfanyl)-7-[3-(methylsulfonyl)pyridin-2-yl]-N-[4-(trifluoromethyl)phenyl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;[7-(3-Ethanesulfonyl-pyridin-2-yl)-2-methylsulfanyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;{5-Chloro-6-[2-(methylsulfanyl)-4-{[4-(trifluoromethyl)phenyl]amino}-5,6,8,9-tetrahydro-7H-pyrimido[4,5-d]azepin-7-yl]pyridin-3-yl}methanol;2-({[(4S)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}oxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylpiperidin-4-yl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(Pyrrolidin-1-ylsulfonyl)phenyl]-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-{[1-(1-Methylethyl)pyrrolidin-3-yl]oxy}-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclopropylethyl)oxy]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclopropylethyl)oxy]-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-2-(tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclopropylethyl)oxy]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexyloxy)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Butyloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexyloxy)-N-(1-methyl-1,2,3,4-tetrahydroquinolin-7-yl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-(1-Methyl-1,2,3,4-tetrahydroquinolin-7-yl)-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-({[(4R)-2,2-Dimethyl-1,3-dioxolan-4-yl]methyl}oxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Tetrahydrofuran-3-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclohexylethyl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Cyclopropylethyl)oxy]-N-[4-(pyrrolidin-1-ylsulfonyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[4-(Pyrrolidin-1-ylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yloxy)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cycloheptyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclopentyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Tetrahydro-2H-pyran-4-yloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Tetrahydrofuran-3-yloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)oxy]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-(Phenyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-(Butyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-oltrifluoroacetic acid salt;2-(Ethyloxy)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-[(Methyloxy)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-aminetrifluoroacetic acid salt;2-Methyl-2-[4-({2-[(methyloxy)methyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl}amino)phenyl]propanenitriletrifluoroacetic acid salt;2-(Methylsulfonyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Phenylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-(phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Phenylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(Phenylmethyl)sulfanyl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)sulfanyl]-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;1-[(4-{[4-(Trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)sulfanyl]propan-2-ol;[2-(2-Methyl-tetrahydro-furan-3-ylsulfanyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethyl-phenyl)-amine;2-[(Phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;1-({7-[3-(Trifluoromethyl)pyridin-2-yl]-4-({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}sulfanyl)propan-2-ol;[2-(2-Methyl-tetrahydro-furan-3-ylsulfanyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;N-[2-Methyl-4-(trifluoromethyl)phenyl]-2-[(phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexylsulfanyl)-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)sulfanyl]-N-[2-methyl-4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;1-[(4-{[2-Methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)sulfanyl]propan-2-ol;2,5-Anhydro-1,4-dideoxy-3-S-(4-{[2-methyl-4-(trifluoromethyl)phenyl]amino}-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl)-3-thiopentitol;2-[(Phenylmethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-(Cyclohexylsulfanyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;2-[(1-Methylethyl)sulfanyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-N-(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;1-({7-[3-(Trifluoromethyl)pyridin-2-yl]-4-[(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}sulfanyl)propan-2-ol;2,5-Anhydro-1,4-dideoxy-3-thio-3-S-{7-[3-(trifluoromethyl)pyridin-2-yl]-4-[(1,4,4-trimethyl-1,2,3,4-tetrahydroquinolin-7-yl)amino]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-2-yl}pentitol;2-(Propylsulfanyl)-N-[4-(trifluoromethyl)phenyl]-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;and2-(1-Methylethyl)-N-(4-pyrrolidin-1-ylphenyl)-7-[3-(trifluoromethyl)pyridin-2-yl]-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-amine;and pharmaceutically acceptable salts thereof, and (b) apharmaceutically acceptable excipient.
 5. A pharmaceutical compositioncomprising: (a) an therapeutically effective amount of a compoundselected from the group consisting ofN-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-pyridin-3-yl}-methanesulfonamide;N-{2-[2-Isopropyl-4-(4-trifluoromethyl-phenylamino)-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepin-7-yl]-phenyl}-methanesulfonamide;N²-(2-Dimethylamino-ethyl)-N²-methyl-N⁴-(4-trifluoromethyl-phenyl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepine-2,4-diamine;N²,N²-Dimethyl-N⁶-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;2-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-N-methyl-isobutyramide;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine;(4-Methanesulfonyl-phenyl)[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;1,1,1-Trifluoro-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;2-{2-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;2-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-1-ol;[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-N²-methyl-3-trifluoromethyl-pyridine-2,6-diamine;2-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;2-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;(3-Fluoro-4-trifluoromethyl-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methyl ester;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid dimethylamide;[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N⁶-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Bromo-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Chloro-phenyl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(1-Methyl-1,2,3,4-tetrahydro-quinolin-7-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine;2-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propionitrile;4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid;N²-Methyl-N⁶-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;2-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;2-Fluoro-4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol;[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N,N-Dimethyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methyl ester;(6-Chloro-5-trifluoromethyl-pyridin-2-yl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid;(1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol;[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid amide;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methylamide;N-Methyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N,N-Dimethyl-2-{4-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁶-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;N²-Methyl-N⁶-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;N²,N²-Dimethyl-N⁶-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(morpholine-4-sulfonyl)-phenyl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(piperazine-1-sulfonyl)-phenyl]-amine;[4-(Morpholine-4-sulfonyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(Piperazine-1-sulfonyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N⁶-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-N²,N²-dimethyl-3-trifluoromethyl-pyridine-2,6-diamine;N⁶-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;[4-(1-Methylaminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;N²-Methyl-N⁶-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;N²,N²-Dimethyl-N⁶-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-3-trifluoromethyl-pyridine-2,6-diamine;1,1,1-Trifluoro-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-{2-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;2-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid;2-Fluoro-4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;(3-Fluoro-4-trifluoromethyl-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N-Methyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;N,N-Dimethyl-2-{4-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;2-{2-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-2-ol;2-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid;2-Fluoro-4-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-benzoicacid methyl ester;2-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-N,N-dimethyl-isobutyramide;N-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-isobutyramide;(6-Methoxy-5-trifluoromethyl-pyridin-2-yl)-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Bromo-phenyl)-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethoxy-phenyl)-amine;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(5-trifluoromethyl-pyrazin-2-yl)-amine;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methylamide;1-{4-[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid amide;(4-Bromo-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(4-Methanesulfonyl-phenyl)-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;(1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(4-trifluoromethanesulfonyl-phenyl)-amine;[4-(2-Dimethylamino-1,1-dimethyl-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(2-Amino-1,1-dimethyl-ethyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;2-Methyl-2-{4-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-propan-1-ol;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid;[4-(1,1-Dimethyl-2-methylamino-ethyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methylamide;[4-(1-Methylaminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-(2-methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid dimethylamide;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid amide;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methyl ester;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid;[2-Morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(pyrrolidine-1-sulfonyl)-phenyl]-amine;(1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol;1-{4-[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1,4,4-trimethyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(1-methyl-1,2,3,4-tetrahydro-quinolin-7-yl)-amine;[2-(2-Methyl-pyrrolidin-1-yl)-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-(6-trifluoromethyl-pyridin-3-yl)-amine;[4-(1-Aminomethyl-cyclopropyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-[4-(1-methylaminomethyl-cyclopropyl)-phenyl]-amine;[4-(1-Dimethylaminomethyl-cyclopropyl)-phenyl]-[2-isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid dimethylamide;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid amide;(1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropyl)-methanol;1-{4-[2-Isopropyl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanol;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methyl ester;[4-(Morpholine-4-sulfonyl)-phenyl]-[2-morpholin-4-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-yl]-amine;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid;1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid methylamide; and1-{4-[2-Piperidin-1-yl-7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ylamino]-phenyl}-cyclopropanecarboxylicacid dimethylamide; and pharmaceutically acceptable salts thereof, and(b) a pharmaceutically acceptable excipient.